SK147297A3 - Piperazino derivatives as neurokinin antagonists - Google Patents

Abstract

The invention relates to compounds of formula (I). These compounds are neurokinin antagonists. These compounds are useful in the treatment of chronic airway diseases such as asthma.

Description

Neurokinin receptors are found in the nervous system, circulatory system, and peripheral tissues of mammals, and therefore participate in many biological processes. Neurokinin receptor antagonists are therefore expected to be used to treat or prevent various mammalian diseases such as asthma, cough, bronchospasm, inflammatory diseases such as arthritis, central nervous system conditions such as migraine and epilepsy, CNS diseases such as anxiety and various gastrointestinal diseases such as Crohn's disease.

In particular, NK-1 receptors have been reported to be involved in microvascular leakage and mucosal secretion, and NK-2 receptors have been associated with smooth muscle contraction, making NK-1 and NK-2 receptor antagonists particularly useful for the treatment and prevention of asthma.

SUMMARY OF THE INVENTION

Summary of the Invention

The present invention relates to compounds of general (I):

wherein each X is independently O, (H, H), NR _d or S;

n is 0 to 2, u is 0 to 2, 1 is 0 to 2; m is 1 and y is 1 to 3, or m is 2 and y is 0; provided that no more than one R _c in the group is present

the formula is other than H;

each R _c is independently H, C 1 -C ₆ alkyl, - (CH ₂ ) _n -R 1 is 1 to 6;

where ηχ

R ₄ is -OR _a , SR _a ,

r) is C 1 -C 6 alkyl or (CH ₂ ) _n OR _and provided that there is no more than one R 6? is other than H;

each R _a and R _b are independently selected from the group consisting of H, C _x to C ₆ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl, or when the R _a and R _b are attached to the same carbon atom, then R _a and R _b together with the nitrogen atom to which they are attached form a 4 to 7 membered ring; R _d is independently selected from the group consisting of H, C 1 -C ₆ alkyl, CN, OR _a , phenyl, substituted phenyl, benzyl, or allyl;

wherein each R 1 and R ₂ are independently H, C 1 -C ₆ alkyl, CF ₃ , C ₂ H ₅ , Cl, Br, I, F, NO ₂ , OR _a , CN, NR _a R _b ,

O Ha

II I —O — C — N — Rb

Rb O i u

N-C-OR

ABOUT

II

-C-R

ABOUT

II

ABOUT

II

-O-CR a

Ra O I II

-NC-Rb-C-OR _a

OR _and II I

-CN- R _b

ABOUT

II —S— FL

In —S — r _b , -SRa>

—S-NHR _a .

and wherein R _a is not H voo

II //

-S — Ra —S — R

Rb o

I N • N-C-OR 0.

or when R 1 and R ₂ are on adjacent carbon ring atoms, then they can form

wherein n ^z is 1 or 2; and each R ₃ is independently H, C 1 -C ₆ alkyl, CF ₃ , C 2 F 5.

ABOUT

II

CR a

OOR _a

-O — C-R a — NR _{b Qr ρ} , θρθ. _OC p ₃ or phenyl;

Ar 1 is heteroaryl or substituted heteroaryl, is heteroaryl or substituted heteroaryl,

each R ₅ is independently selected from the group consisting of H, OH,

^{O-C-R, and}

C 1 -C ₆ alkyl, - (CH ₂ ) n 1 -R 1 where n 1 is 1 to 6 provided that when n 1 is 1, R ₄ is not OH or NR _and R _b , and also that when R ₅ is C 1 to C 6 C ₆ alkyl then two R ₅ may be attached to the nitrogen to form a quaternary salt; and n ₅ is 1 or n ₅ is 2, with the proviso that each n ₅ is independently C 1 -C ₆ alkyl;

pi and p ₂ are each independently 1-4, provided that when a and p ₂ with 2 to 6;

R ₆ is heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted-heterocycloalkyl,

X 3 is O, NR _d or S;

or a pharmaceutically acceptable salt thereof.

All variables in the above samples, such as Z, R 1, R _2, and R _3, have the same meaning throughout the application unless explicitly stated otherwise.

Preferred compounds of the present invention are compounds of formula (I) wherein X is O, (H, H) and at least one X is O.

preferred They are Too compound of of formula (I), in which both X are 0. preferred They are Too compound of of formula (I), in wherein 1 is 0 , m i is 1 and y is 1. preferred They are Too compound of of formula (I), in wherein n is 1 and u is 0 • Preferred are Too compound of of formula (I),

in which Ari is

wherein Q is N or CH;

each Χχ is independently O, S or NR _a ;

each X ₂ is independently ¹ CH or N; and n ₄ is 0 or 1.

Also preferred are compounds of formula (I) wherein Ar ₂ is

Also preferred are compounds of formula (I),

Also preferred are compounds of formula (I) wherein Z is

N,

Also preferred are compounds of formula (I) wherein both X. are 0, 1 is 0, m is 1, y is 1, n is 1, u is 0 and Ar 1 is

Also preferred are compounds of formula (I) wherein Ar ₂ is

wherein n ₄ is 0 or 1.

Also preferred are compounds of formula (I),

(I),

Also preferred are compounds of formula wherein Z is

N.

Also preferred are those wherein R ₆ is compounds of formula (I) z

Also preferred are compounds of formula (I ^z ) wherein R ₆ is

Examples of compounds of the present invention are compounds of the formulas:

or a compound selected from the group consisting of

F>

CH _a //

Cl Cl ch ₃

Cl Cl

Cl Cl

Cl Cl

Cl

Cl

I

H _and C ³ ₊ O z -> O ν ^ ν

DCI

^H 2 O ₊ O 2 in ^{CF 3} n 2 -nn

HO z — λ O, ^CF3

CF,

H O rs NJ ^ -NN

ch ₃ and ₃

OCH,

MeO

MeO

OH

Rc = _CH3, isobutyl, - (CH _{2) n} -COOH. - (CH 2 OH, - (ΟΗ ^, - ΟΟΝΗ; .. n, = 1-6

R = CH _3, butyl / - _(CH? J _n -COOH.

- (CH 2) _n -OH. - (CH ₂ ) n -, CONH ₂ , n, = 1-6

Rc = - (CH ₂ OH) - (CH ₂ ) _n , -COOH. R _{c =} - (CH 2 OH) - (CH ₂ ) _{n 1} -COOH.

- (CH ^ nj-COOH - _{(CH2) n,} -CQOH n = 1-6, _n2 = 2-6 _{n, V6 n _? = 2. 6,} or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically acceptable carrier.

The invention relates to a method of inducing neurokinin antagonism comprising administering to a mammal in need thereof a neurokinin antagonist effective amount of a compound of formula (I).

The invention relates to a method for the treatment of chronic respiratory diseases such as asthma and allergy, inflammatory diseases such as inflammation of the intestines, psoriasis, fibrocitosis, osteoarthritis and rheumatoid arthritis, migraines, central nervous system diseases such as depression, psychosis, dementia and Alzheimer's disease, Down syndrome. , neuropathy, multiple sclerosis, ophthalmic diseases, conjunctivitis autoimmune diseases, transplant rejection, systemic lupus erythematosus, gastrointestinal tract diseases such as Crohn's disease and ulcerative colitis, kidney function disorders, circulatory diseases such as angina, Raynaud's disease. In particular, the invention relates to a method of treating asthma comprising administering an antiasthmatically effective amount of a compound of formula (I) to a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, alkyl means a straight or branched saturated hydrocarbon chain of from 1 to 6 carbon atoms. The number of carbon atoms may be indicated. For example, _{a Cl-6} alkyl means straight or branched saturated hydrocarbon chain comprising from 1 to 6 carbon atoms.

Alkenyl means straight or branched alkenyl having 2 to 6 carbon atoms. The number of carbon atoms may be indicated. For example, C ₂ to C ₆ alkenyl means a straight or branched alkenyl consisting of 2 to 6 carbon atoms.

Alkynyl means straight or branched alkynyl of 2 to 6 carbon atoms. The number of carbon atoms may be indicated. For example, C ₂ to C ₆ alkynyl 'means straight or branched alkynyl consisting of 2 to 6 carbon atoms.

As used in the present invention, a thick dark line means a chemical bond extending above the plane of the paper. The dashed line means a chemical bond pointing below the plane of the paper.

As used in the present invention,

for example, R 1, R ₂ and R ₃ may each have naphthyl groups mentioned on both cycles.

Asymmetric centers exist in the compounds of formula (I) of the present invention. As a result, the compounds of formula (I) contain stereoisomers.

All such isomeric forms and mixtures thereof are within the scope of the present invention. Unless expressly stated otherwise, the preparation methods described in the present invention result in products that contain all possible structural isomers, although it is understood that the physiological reaction may vary according to the stereochemical structure. Isomers are obtained using conventional techniques such as fractional crystallization, preparative plate or column chromatography on silica gel, alumina, reverse phase or HPLC.

The enantiomers may be separated, if desired, by derivatization or salt formation with an optically pure reagent and resolution by one of the methods described. Alternatively, enantiomers can be separated by chromatography on a chiral support.

The compounds of formula (I) may exist in insoluble as well as in soluble forms, including hydrated forms, for example hemihydrate. In general, the soluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the insoluble forms for the purposes of the present invention.

Compounds of formula (I) which contain a basic group such as -CH ₂ NH ₂ form pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts are non-toxic salts formed by the addition of a stoichiometric amount of a mineral acid such as HCl, HBr, I-bSCh, H 3 PO 4 or an organic acid such as acetic, propionic, valeric, oleic, palmitic, stearic, lauric, benzoic, lactic, ptoluenesulfonic, methanesulfonic, lemon, maleic, fumaric, amber, and the like, to a suitable compound of the present invention.

General methods of preparation

The compounds of the present invention are prepared by one of the following methods. As used herein, LT means room temperature. Unless explicitly stated otherwise, the variables in the general formulas are as defined above. The starting materials and reagents used in the methods and examples are known or can be synthesized by known methods.

As used herein, the term substituted phenyl means

R 30 wherein R 1, R ₂ and R ₃ are as defined above.

Substituted means substituted by R _x, R ₂ and / or R _3rd Aryl means phenyl, naphthyl, idenyl, tetrahydronaphthyl, indanyl, anthracenyl or fluorenyl.

Halogen means fluorine, chlorine, bromine or iodine atoms. Heterocycloalkyl refers to four to six membered saturated rings containing 1 to 3 heteroatoms independently selected from the group consisting of -O-, -S-, and N (R ⁶ ) provided that the remaining ring members are carbon. Examples of heterocycloalkyl rings are tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. R ⁴ -heterocycloalkyl means those groups in which the substituted ring carbon atoms carry an R ⁴ substituent.

Heteroaryl means five to ten membered single or benzo-fused aromatic rings containing 1 to 4 heteroatoms independently selected from the group consisting of -O-, -S- and -N =. Examples of single ring heteroaryl groups are pyridil, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pirazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzo-fused heteroaryl groups are quinolinyl, thianaphthenyl and benzofurazanyl. Also included are NOxides of the nitrogen-containing heteroaryl groups. All positional isomers, for example 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl, are contemplated.

Where R ² and R ³ form a ring and other heteroatoms are present, the rings do not contain oxygen and / or sulfur atoms or three adjacent heteroatoms adjacent. Typical rings thus formed are morpholinyl, piperazinyl and piperidinyl.

As used herein, the term BOC means t-butoxycarbonyl.

As used herein, the term Ph means phenyl.

As used in the present invention, the term LT means room temperature.

As used in the present invention, the term parallel synthesis means preparing individual chemical compounds in a single dose, for example 20, 30 or even 100 identical reactions, usually on a single substrate, but using a different reagent in each vessel. Such reagents are always from the same group, in this case either carboxyl groups or organic amines in any group of parallel reactions. The conditions used for each reaction are the same as those described in the examples, except for those where simpler processing is used, simple washing with either acid or base and then water. The presence of the product is detected by thin layer chromatography (TLC) using known products as standards. Further characterization is generally performed by a HPLC / MS combination. These materials are used without further purification for biological testing.

As used herein, R _c and R _c are independently selected from the group consisting of H, C 1 -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, unsubstituted or substituted phenyl, and unsubstituted or substituted benzyl.

The starting materials in the known methods below are either known or can be prepared by known methods. In particular, the following compounds are known or can be prepared by known methods: diamine of formula (A), compounds of formula (A), (VI), (VII), (X), (XI), (XIV), (XVIII) , (XIX), (XXa), (A ^z ), (XXV) and ZH equals 32 as esters of formula (IX) and compounds:

Method 1

When Ar _{2 is an} aromatic group that bears no substituent I or Br, the following method can be used to prepare useful intermediates (IV):

Ph Ph 'z

with a reagent in a dry ether type solvent such as THF catalysed by a transition metal leads to the aryl substituted pyrazine of formula (II ^Z ). The catalyst, [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride, is the preferred reagent for this reaction. When Ar ₂ carries no halogen as a substituent, reduction of a compound of formula (II ^Z ) by catalytic hydrogenation with, for example, palladium (II) acetate, preferably in acetic acid, as a solvent, results in preferential reduction of the pyrazine ring, provided the aromatic ring is not reduced resulting in a compound of formula (II). Similarly, 10% (w / w) Pd on carbon (Pd-C) may be used in an alcoholic solvent, preferably methanol, or without the addition of a small amount (1 to 5 equivalents) of acetic acid. A reaction time of 1 to 24 hours for this reaction is post 33 at room temperature using 606 MPa).

with the proviso that the reaction is carried out at ambient temperature or slightly higher (up to 50 ° C) hydrogen pressure of 1 to 6 atmospheres (0.101 MPa to 0),

Ar,

Pd (OAc) _:

Ho / AcOH

Ar ₂ u

(H)

An intermediate of formula (II) from a compound of formula (II ^Z ) when Ar ₂ contains halogen atoms:

It is possible to even reduce with a strong hydride ion donor, preferably lithium tetrahydroaluminate (LAH) or doisobutyldihydroaluminate (DIBAL-H) in an ether solvent such as ether, THF or dimethoxyethane (DME).

Selective alkylation of the compound of formula (II) is possible at low temperatures. Thus, treatment of a compound of formula (II) with a substituted arylalkyl halide of formula (III) wherein 1 is 0 to 2 gives a 4-substituted derivative of formula (IV). Suitable conditions include the use of a halogenated solvent such as CH ₂ Cl ₂ at low temperature. Suitable temperatures are -78 ° C as the starting temperature, and until the reaction is complete after several hours, the reaction mixture is allowed to gradually warm to room temperature. The reaction is catalyzed by the addition of an equivalent amount of an organic base such as triethylamine and diisopropylethylamine (Hunig's base).

Method 2

When Ar ₂ contains one or more halogen atoms on the aromatic ring and the other groups are as in Method 1, then an alternative route to the compound of formula (IV) is preferred. This process can also be used to prepare compounds wherein 1 is outside the range of 0 to 2. The monoprotected diamine of formula (A), preferably with BOC anhydride or other agents known to introduce a t-butoxycarbonyl protecting group in the an alcoholic solvent such as methanol, preferably at -10 ° C, leads to a compound of formula (V).

NH

NHBOC (A)

These compounds are used to effect reductive amination with an aldehyde of formula (VI) to give an amine of formula (VII). (In the structures of formulas (A), (V), (VII) and (IX), R _{c is} bonded anywhere between two nitrogen atoms. About the cyclic structures of formula (IV A) below, R c is bonded at any available position of the cycle, which is occupied by carbon and is between two nitrogen atoms.)

Suitable conditions for this type of reaction include the use of an alcoholic solvent, preferably methanol, which is slightly acidified with a weak organic acid, such as acetic acid, and a reducing agent known to be suitable for reductive amination, preferably sodium cyanoborohydride NaBH ₃ CN.

(CHV-N

(Vil)

Reaction of a compound of formula (VII) with a phenacyl halide derivative of formula (VIII) in which Ar ₂ is preferably a halogenated aromatic ring, but may be any claimable aromatic ring, in the presence of an organic base such as diisopropylethylamine also known as Hunig a base, in an ether solvent such as THF, to give intermediates of formula (IX).

NH-BOC (VII)

Removal of the BOC protecting group with a suitable acid catalyst, such as trifluoroacetic acid, is followed by intramolecular reductive amination under the conditions described for the preparation of compounds of formula (VII), resulting in compounds of formula (VI A).

Method 3

An alternative route to compounds of the present invention wherein 1 is 0 to 2 is as follows. By standard coupling of an N-protected amino acid of formula (X) wherein Ar ₂ is as defined above, for example Ar ₂ -CH (NHChran) CO ₂ H, with a glycine ester or an amino acid ester derivative with an

rc

Ibn xoor · (R ⁷ is a C ₂ to C ₄ alkyl, such as ethyl ester of formula (XI), when the abbreviation Et is ethyl) form a dipeptide of formula (XII). A suitable protecting group is BOC, but many others can be used. Other glycine esters may also be used. Standard coupling techniques can be used, such as the use of N-hydroxybenzotriazole (HOBT) and a water-soluble carbodiimide such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (DEC) in a non-hydroxylic solvent such as CH ₂ Cl ₂ , DMF or mixtures thereof. The reaction is preferably carried out at or below room temperature and takes from 1 to 40 hours, depending on the substrates.

Deprotection under standard conditions, followed by reaction of the product with a base, results in cyclization to the diketopiperazine of formula (XIII). Suitable conditions for BOC removal are well known in the art and include catalysis of trifluoroacetic acid (TFA). A suitable base for cyclization is the alkali metal salt of the alcohol in the alcohol used as solvent. For example, a solution of sodium ethoxide in ethanol may be used. The temperature is preferably around RT but may be slightly higher or lower, from 0 ° to ^40: 'C. The reaction usually takes several hours. A suitable reaction time is 1 to 24 hours.

(XH)

The reduction of the diketopiperazine of formula (XIII) to the compound of formula (II) may preferably be carried out with a strong hydride reducing agent such as LAH or a solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene (also known as Red-Al®) or BH complex. ₃ .S (CH _{3) second} Suitable solvents for this reaction are DME and other higher boiling ethers, since the reaction is carried out at elevated temperatures, from 50 ° C to 110 ° C, preferably at 90 ° C.

Alternatively, the compound of formula (II) can be prepared according to the following reaction scheme (J. Med. Chem., 9, 191 (1996)). As used in the present invention, L is any readily removable ester or C ₇ alkyl, preferably methyl or ethyl. halogenation

Ar ₂

X

X = Cl, Br, I residue such as C 1

Ar.

u + 1 COO-L

A compound of formula (II) can be converted to a compound of formula (IV) by the method described in Method 1 or Method 6.

Method 4

The intermediates of the formulas (IV) or (IV A) obtained by any of the processes described can be further processed as follows. Schemes will show a compound of formula (IV A). Reaction of a compound of formula (IV A) with an activated haloacid, generally with an acid halide of formula (XIV), wherein Hal is Cl, Br or I, resulting in an acylated derivative of formula (XV) when m is 1 then it is a compound of formula (I). An organic base is used to remove the hydrogen halide formed in the reaction, a suitable base being triethylamine (TEA) and Hunig's base. Suitable reaction media are halogenated solvents such as dichloromethane and chloroform. The reaction is preferably carried out at low temperature at least initially. Suitable temperatures are -50 ° C to -80 ° C. Later, it may be appropriate to continue the reaction at room temperature to ensure complete completion of the reaction.

Hal- (CH) YCO-Hal

RC (XIV)

rc

Reaction of the halogenated amides of formula (XV) with an amine Z-H results in the product of formula (XVI), compounds of the present invention wherein X is O and m is 1.

Compounds of formula (XVI) have been modified to show that these products can be prepared from compounds of formula IV A as well as from compounds of formula IV. Suitable solvents for this reaction are halogenated hydrocarbons such as dichloromethane and the organic base present absorbs the resulting hydrogen halide. Hunig's base is also suitable. The reaction is carried out at room temperature, with a suitable temperature of 0 ° C to 40 ° C. The reaction takes from 1 hour to 48 hours.

Method 5

Compounds of formula (XVI) wherein y 0 can be converted to other compounds of the present invention of formula (XVII) by controlled reduction.

Suitable reducing agents for this transformation are borane-dimethylsulfide complex as well as other less selective agents such as LAH (provided that no other LAH reactive group is present), Red-Al® and diborane in ether. Temperatures for reducing compounds of formula (XVI) with borane-dimethylsulfide complex are from room temperature to the boiling point of a reagent solution in THF (80 ° C).

Method 6

Intermediates of formula (XVIII) may be selectively acylated by coupling with an acid of formula (XIX). Standard coupling techniques can be employed, for example, using HOBT, a water-soluble carbodiimide such as DEC and an organic base such as triethylamine in a hydroxyl-free solvent such as dichloromethane at an initial temperature of -20 ° C. The mixture can be warmed to

(XVIII)

Compounds of formula (XX) may be further acylated with an acyl halide of formula (XXa). The reaction is preferably carried out at -78 ° C, for 1 to 12 hours, in a halogenated solvent such as dichloromethane or the like. An organic tertiary amine is used to absorb the hydrogen halide formed in the reaction. Suitable amines are triethylamine and Hunig's base. As used herein, hydrogen halide is hydrogen chloride, hydrogen bromide or hydrogen iodide.

rc

Compounds of formula (XXI), i.e. compounds of formula (I) wherein m is 1, y = 1 to 3, 1 = 0 to 2, can be used for the next reaction without isolation. Additional amounts of organic base, for example, Hunig's base, and Z-H are added to the mixture at -78 ° C. The reaction is terminated by allowing the mixture to warm to room temperature overnight to give compounds after standard work-up and purification.

\

RC (XXI)

RC (XXII)

Compounds of formula (XXII) wherein y-1 to 3 can be converted to other products of formula (XXIII) by controlled reduction.

Suitable reducing agents for this transformation are borane-dimethylsulfide complex as well as other less selective agents such as LAH, Red-Al® and diborane in ether or another non-reactive solvent such as THF. The temperature for reduction with borane-dimethylsulfide complex is the boiling point of the solution, which is 80 ° C, when the reaction is complete in 2 hours to 48 hours depending on the particular substrate.

Some of the ZH substrates for the alkylation reaction were synthesized from 4-amino-1-benzylpiperidine (A) by first converting to the t.-BOC protected derivative (B) and removing the benzyl group by hydrogenolysis on a suitable catalyst such as Pd ( OH) ₂ to give the t-BOC protected piperidine (C). Further processing of this piperidine can be accomplished by either alkylation or reductive alkylation depending on the availability of reagents for these reactions.

Reaction of intermediate (C) with an aldehyde or ketone (D) under reductive alkylation conditions such as methanol and in the presence of NABH ₃ CN with a sufficient amount of AcOH (acetic acid) to afford a suitable rate of reaction affords an amine (E) from which The t-BOC group is removed, for example, with 4 N HCl in dioxane and neutralized, for example, with an aqueous solution of NaOH to give a compound of formula (F).

The same product (E) can be prepared from (C) by alkylation with a halogen derivative (G) where Hal is Cl, Br or I. Other activated leaving groups such as mesylates or tosylates can also be used for this reagent. The reagent is preferably primary, but the reaction can often also be carried out with secondary derivatives.

The alkylation product (E) can be reacted further to give 4-aminopiperidine (F), which is one of the preferred forms of Z, which can be used to convert a compound of formula (XXI) to a compound of formula (XXII). .

nh ₂

Method i

The acylated derivatives of general formula 6 can be reduced to the derivatives of the general formula XXIV.

of formula (XX) from a saturated alkyl

(XXIV)

The method of carrying out the conversion is the same as described in Method 6 for converting a compound of formula (XXII) to a compound of formula (XXIII). A preferred reagent is borane-dimethylsulfide complex.

Treatment of an intermediate of formula (XXIV) with an acyl halide of formula (XXV) at -78 ° C affords an amide of formula (XXVI). The reaction is preferably carried out in a halogenated solvent such as methylene chloride in the presence of an organic base which removes the hydrogen halide formed. A suitable base is Hunig's base. The product, a compound of formula (XXVI), can be used without isolation for the next step.

c · (XXIV)

CHjíCH)) —Ar ·!

The halo derivative of general formula (XXVI) can be used without isolation in reaction with the amino compound Z-H. An additional equivalent amount of a suitable organic base, such as Hiinig's base, is added to the mixture to remove the resulting hydrogen halide. The reaction is initially carried out at -78 ° C, but then allowed to gradually warm to room temperature to quench. The product, a compound of formula (XXVII), is isolated by conventional techniques and purified by flash chromatography.

R ·

CH ₂ (CH), Ah

ZH 4 H ₂ (CH), -Ab

(XXV11) (CIHh

An alternative route to compounds of structure (XXII) also starts from a compound of formula (XVIII). First, reaction with an amino protecting agent, preferably BOC anhydride, yields the N-t-butyloxycarbonyl derivative of general formula (XXVIII).

As well as elsewhere, reaction occurs preferentially at the nitrogen atom further away from the Ar _second Reaction of this intermediate with an agent of formula (XXa) as described above results in a halogen derivative of formula (XXIX). Reaction of the compound of formula (XXIX) with ZH, again as described above, yields intermediate (XXX) which can be deprotected to give the compound of formula (XXXI). Suitable reagents are trifluoroacetic acid and HCl.

(XXVIII) + (XXa) -Hal

N N- ^ o-

Ar ₂

U (XXIX)

Ali (XXXI)

Reaction of a compound of formula (XXXI) with a carboxylic acid (XIX) under the coupling conditions described above results in the products of formula (XXII).

Method 7a

The synthesis of compounds of the present invention wherein the aromatic group Ar ₂ or the aromatic group Ar ₂ and its side chain is located in alternating positions on the cycle relative to compounds of formula (XXII) (i.e. compounds of formula (C)) is can be carried out using compounds of formula (XXVIII) from Method 7 as starting materials. Coupling of compounds of formula (XXVIII) with any of the acids of the present invention under standard coupling conditions, for example using HOBT, Et ₃ N and DEC in CH ₂ Cl ₂ , yields an intermediate of formula (A). Removal of the t-BOC or other protecting group under standard conditions affords the free amine of formula (B). Acylation (B) and further reaction with ZH of the procedure described in Method 6 for converting a compound of formula (XX) via a compound of formula (XXI) to a compound of formula (XXII) affords a compound of formula (C) of the present invention.

(XXVIII)

ri

Method 8

The process for introducing the R _c group into the side chain of a compound of the present invention begins with the preparation of a compound of formula (XX). The compound may be coupled to a suitably protected amino acid derivative of formula (XXXII) in which the t-BOC group is used as a representative protecting group. The use of relatively reactive coupling agents such as ΒΟΡ-Cl of formula (XXXIII) is preferred and the reaction is carried out under standard coupling conditions well known to those skilled in the art. Suitable conditions include the use of CH ₂ Cl ₂ and / or DMF as a solvent with triethylamine or Hilnig base, from a starting temperature of 0 ° C to room temperature. Workup yields the protected intermediate of formula (XXXIV).

In the case of compounds of formula (XXXIV) in which the N-protecting group is t-BOC, conventional conditions for the removal of such groups can be used to release the amino group. Different concentrations of CF ₃ CO ₂ H in CH ₂ Cl ₂ are usually sufficient. For some substrates, dilute solutions (e.g. 2 N) are sufficient, in some cases more concentrated solutions up to TFA in the substance may be required. Other N-protecting groups may be used and may be removed by methods well known in the art. An example is the use of N-Cbz, which can be removed either acid or hydrogenolytically. The deprotection resulted in an amine intermediate of formula (XXXV).

+

XXXII.

XXXIII

(XXXV)

NH-BOC is about

Fo

I

Cl

XXXIII

Conversion of the intermediate of formula (XXXV) to the compounds of the present invention is accomplished by reductive alkylation.

The Z moiety is introduced into the molecule by an aldehyde or ketone in which the Z moiety is present on a carbon atom that is attached to the amino group of formula (XXXV). An example of such an intermediate is a compound of formula (XXXVI).

After the reaction, this group becomes a Z group of the compounds of the present invention, i.e., the Y-NH group shown in the compounds of formula (XXXVII)

R _c

The conditions for this reductive amination are known in the art and are exemplified by the use of NaBH ₃ CN in MeOH with the addition of several equivalents of acetic acid. The reaction is carried out at room temperature and allowed to react overnight. The product is isolated by standard means such as decomposition of excess reagent with H ₂ O and extraction of the product into an organic solvent such as CH ₂ Cl ₂ or a mixture of Et ₂ O and CH ₂ Cl ₂ .

Using the procedures described or known to those skilled in the art, it is possible to prepare all compounds of formula (I) according to the present invention. For example, it is possible to obtain compounds of formula (I) of the present invention in which the group R _{c is} on different carbons of the piperazine ring.

The in vitro and in vivo activity of the compounds of formula (I) was determined using the following procedures.

In vitro procedure for determining NK _X activity

Test compounds were tested for their ability to inhibit NK _X activity of agonist substance P in isolated guinea pig vas deferens. Freshly cut vas deferens removed from male Hartley guinea pigs (230 g to 350 g) were immersed in a 25 ml tissue bath containing Krebs Henseleit solution heated to 37 ° C and saturated in a constant manner with 95% (v / v) O ₂ and 5 gas. % of CO ₂ . The tissues were adjusted to 0.5 g and allowed to equilibrate for 30 minutes. The tissues were then subjected to electrical pole stimulation (Grass S48 Stimulator.) Every 60 seconds, at an intensity that caused the tissue to contract to 80% of maximum capacity. All reactions were recorded isometrically using a Grass force displacement transducer (FT03) and a Hardvard electronic recorder. Substance P inhibits the electrical field-induced contraction of guinea pig vas deferens. In unpaired studies, all tissues (also drug treated tissues) were exposed to cumulative54 concentrations of substance P (1 x 10 ^-10 M to 7 x 10 ^-7 M). The concentrations of test compounds were added to the separate tissues and these were allowed to equilibrate for 30 minutes before the P concentration concentration response curve was determined. At least 5 separate tissues were used for both the control and the individual drug concentrations for each drug test.

Inhibition of substance P was demonstrated by shifting its dose concentration curve to the right. These shifts were used to determine the pA ₂ value, which is defined as the negative logarithm of the molar concentration of inhibitor that required the use of twice the agonist concentration to elicit the desired response. This value is used to determine the relative agonist effect.

NK ₂ test of isolated hamster trachea

The methodology and characterization of hamster trachea responses to neurokinin agonists as reported by the NK ₂ monoreceptor assay is described in CA Maggi, et al., Eur. J. Pharmacol. 166 (1989) 435 and JL Ellis et al., J. Pharm. Exp. Ther. 267 (1993) 95.

Continuous isometric tension monitoring is performed using a Grass force displacement transducer (FT03) connected to a Buxco Electonics preamplifier embedded in the Graphtec Lineacorder Model WR 3310.

Male Charles River Hamsters LAK: LVG (SYR), weighing 100 g to 200 g, were stunned and then sacrificed by tactactomy and their heart removed. The cervical portion of the trachea was collected in Krebs buffer at pH 7.4 at room temperature, saturated with a gas consisting of 95% (v / v) O ₂ and 5% (v / v) CO ₂ , and purged of adjacent tissue. The portions were cut into two 3 mm to 4 mm long circular portions. The tracheal rings were suspended from the transducers and anchored with stainless steel hooks and 6-0 silk in 15.0 ml aqueous organic bath. The bath was filled with Krebs buffer, pH 7.4, maintained at 37 ° C and continuously saturated with a gas consisting of 95% (v / v) O ₂ and 5% (v / v) CO ₂ . The tracheal rings were placed under 1.0 g of initial tension and equilibrated for 90 minutes with four immunizations of 1 μΜ NKA, washed and re-equilibrated at 20 minute intervals. 30 minutes of vehicle pretreatment was followed by cumulative additions of NKA purge doses (3 nM to 1 μΜ final concentration, 5 minute intervals). The overall NKA reaction was followed by a 15 minute wash and relax period. After 30 minutes pretreatment with the test compound or vehicle, cumulative additions of NKA flush doses (3 nM to 1 μΜ final concentration, if necessary, intervals between additions of 5 minutes) were followed. The total NKA response was followed by -1 mM carbachol immunization to obtain a maximal voltage response in each tissue.

Tissue responses to NKA were recorded as a positive displacement of the pen above the baseline and were converted to gram stress by comparison to standard weights. Reactions were normalized as% of maximum tissue tension. ED ₅₀ were calculated for NKA from control and dose response reactions and compared. Test compounds resulting in an agonist dosing ratio> 2 at test concentrations of 1 μΜ (i.e. pA ₂ > = 6.0) are considered active. Additional reaction data for the active substances can be obtained by calculating the expected apparent pA ₂ value. pA ₂ is calculated by determining K i by the procedure described by Furchgott (where pA ₂ - log K _if RF Furchgott, Pharm. Rev. 7 [1995] 183) or by Shild graph analysis (O.

Arunklakshana and H.O. Shild, Br. J. Pharmacol. 14 [1959] 48) as long as we have enough data.

Effect of NKi agonists on Substance P-induced air microvascular penetration in guinea pigs

Studies were conducted on male Hartley guinea pigs weighing 400 g to 600 g. Animals were given food and water as needed. Animals were anesthetized by intraperitoneal injection of dialurethane (0.1 g / ml dialylbarbituric acid, 0.4 g / ml ethyl urea and 0.4 g / ml urethane). The trachea was cannulated under the larynx and the animals were connected to a Harward rodent respirator to force them to breathe (V _T = 4 ml, f = 45 breaths / minute). The jugular vessel was cannulated for drug administration.

The Evans blue staining technique (Danko, G. et al., Pharmacol. Commun., 1, 203-209, 1992) was used to measure airway microvascular leakage (AML). Evans Blue (30 mg / kg) was administered intravenously and Substance P (10 µg / kg) was administered intravenously 1 minute thereafter. After five minutes the thorax was opened and a blunt needle was inserted into the aorta. A cut was made through the right ventricle and the blood was expelled by washing 100 ml of a saturated aqueous sodium chloride solution with an aortic catheter. The lungs and trachea were removed as a whole, trachea and bronchi were then dried with filter paper and weighed. Evans blue was extracted by incubating the tissue at 37 ° C for 18 hours in 2 ml formamide in sealed tubes. The absorbance of the formamide dye extracts was measured at 620 nm. The amount of dye was calculated by interpolation from a standard Evans blue curve in the range of 0.5 µg / ml to 10 µg / ml in formamide. The dye concentration was expressed as ng dye per mg wet weighted tka57 blue. Test compounds were suspended in cyclodextran vehicle and administered intravenously 5 minutes before administration of substance P.

Measurement of NK ₂ activity in vivo

Male Hartley guinea pigs (400 g to 500 g) with access to water and food according to their needs were anesthetized by intraperitoneal injection of 0.9 ml / kg dialurethane (content 0.1 g / ml dialylbarbituric acid, 0.4 g / ml ethylurea) and 0.4 g / ml urethane). After anesthesia, cannulas were implanted into the tracheal, oesophageal and jugular vessels to allow mechanical breathing, measurement of oesophageal pressure and drug delivery.

The guinea pigs were placed in a whole-body plethysmograph and the catheters were connected to the outlets of the plethysmograph wall. The airflow (Validyne Northridge CA, model MP45-1, range ± 2 cm H ₂ 0 was measured using a differential pressure transducer when measuring the pressure through a wire screen that covers a hole in the wall of a 1 inch (2.54 cm) plethysmograph. The airflow signal was electrically integrated into the volume proportional signal Transpulmonary pressure was measured as the differential pressure between trachea and esophagus using a differential pressure transducer (Validyne Northridge CA, model MP45-1 range ± 20 cm H ₂ O). transpulmonary pressure signals were monitored using a pulmonary analysis computer (Buxco Elektronics, Sharon, CT, model 6) and were used to derive pulmonary resistance (R _L ) and dynamic pulmonary compliance (C _Dy n) ·

Bronchoconstriction caused by NKA

Increased intravenous doses of NKA were administered at half (0.01 pg / kg to 3 pg / kg) intervals, allowing pulmonary me58 chanic to return to baseline between doses. Peak bronchoconstriction occurred 30 seconds after each dose of agonist. The dose response was stopped when C _Dy n is reduced to 80% to 90% from baseline. A single dose response to NKA was performed in each animal. Test compounds were suspended in cyclodextran vehicle and administered intravenously 5 minutes prior to NKA dose response.

NKA dose response curves were constructed for each animal by expressing the percent increase in R _L or decrease in C _Dyn relative to the logarithm of the agonist dose. NKA doses that increase R ₁ by 100% (R _L 100) or decrease C _Dyn by 40% (C _Dyn 40) from baseline values are obtained by logarithmic linear interpolation of dose response curves.

Neuroconin Receptor Binding Assay (s)

Hamster ovary cells transfected with human neurokinin 1 (NK1) coding regions of human neurokinin 2 (NK2) receptors were grown in Dulbecco's minimal essential medium supplemented with 10% fetal bovine serum, 0.1 mM non-essential amino acids, 2 mM glutamine, 100 units / ml. penicillin and streptomycin and 0.8 mg G418 / ml at 37 ° C in a humidified atmosphere containing 5% (v / v) CO ₂ .

Cells were washed from the T-175 flasks with sterile 5 mM EDTA in phosphate buffered saline. Cells were collected by centrifugation and washed with RPMI medium at 40 ° C for 5 minutes. The pellets were resuspended in Tris-HCl (pH 7.4) containing 1 μΜ phosphoramidone and 4 µg / ml chymostatin at a cell density of 30 x 10 6 cells / ml. The suspension was then homogenized in a Brinkman Polytron (set 5) for 30 seconds to 45 seconds. The homogenate was centrifuged at 800 x g for 5 minutes at 4 ° C to give unbroken cells and nuclei. The supernatant was centrifuged in Sorvall RC5C at 19,000 rpm. (44.00 x g) for 30 minutes at 4 ° C. The pellet was resuspended, the protein assay (BCA) portion was removed, and washed again. The obtained pellet was stored at -80 ° C.

To determine receptor binding, 50 µΐ [ ³ H] of substance P (9-Sar, 11-Met [02])) was 41 Ci / mmol specific activity (Dupont-NEN) (0.8 nM for NK-1 assay (or [ ³ H] Neurokinin A (specific activity 114 Ci / mmol) (Harvest) (1.0 nM for NK-2 assay) added to tubes containing buffer (50 mM Tris-HCl (pH 7.4) with 1 mM MnCl ₂₎ and 0.2% bovine serum albumin) and DMSO or test compound Binding is initiated by the addition of a 100 µΐ membrane (10 µg to 20 µg) containing a human NK-1 or NK-2 receptor in a total volume of 200 µΐ. The reaction was terminated by rapid filtration through Whatman GF / C filters pre-wetted with 0.3% polyethyleneimine, washed twice with 3 mL of 50 mM Tris-HCl (pH 7.4), added to 6 mL of liquid scintillation solution and quantified by liquid scintillation spectrometry in an LKB 1219 RackBeta meter. Non-specific binding is determined by adding either 1 μΜ CP-99994 (NK-1) and or 1 μΜ SR-48968 (NK-2) (both synthesized by the Schering-Plow Research Institute Chemical Department). IC 50 values were determined from binding competition curves and Ki values were determined by Cheng and Prusoff, provided that 0.8 nM for NK-1 receptor and 2.4 nM for NK-2 receptor were experimentally determined.

For all compounds of the present invention, NK _X binding is in the range of 0% to 100% inhibition at a concentration of 1 μΜ. For all compounds of the present invention, NK ₂ binding is in the range of 0% to 100% inhibition at a concentration of 1 µΜ. It is understood that while NK binding for certain compounds of the present invention is so low at 1 μΜ at 60% that it is 0%, at higher concentrations these NK compounds have binding inhibitory activity.

The K i of a compound is that concentration at which the compound causes 50% inhibition of either NK _X or NK ₂ . For compounds of the present invention which have greater than 50% inhibition of NK 1, K i values for NK 1 have been determined. K i values for NKi for such compounds fall within the range of 0.1 nM to μΜ.

For compounds of the present invention that have greater than 50% inhibition of NK ₂ , K i values for NK ₂ were determined. K ₂ values for NK ₂ for such compounds fall within the range of 0.1 nM to 1 μΜ.

Compounds of formula (I) exhibit NK 1 and NK ₂ antagonist activity of varying degrees, for example certain compounds have strong NK 1 antagonist activity but weaker NK ₂ antagonist activity. Others are strong NK ₂ antagonists but weaker NK 1 antagonists. While compounds with approximately the same effects are preferred, the use of compounds with unequal NK 1 / NK ₂ antagonist activity is also within the scope of the present invention, if clinically appropriate.

Certain compounds of formula (I) was found to be a NK receptor NK ₂ and _X, and are therefore useful in treating conditions caused or aggravated by the activity of the receptor.

The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The compounds of the present invention may be administered in conventional oral dosage forms such as capsules, tablets, powders, suspensions or solutions, or in injectable dosage forms such as solutions, suspensions or powders for reconstitution. The pharmaceutical compositions can be prepared with conventional ex61 excipients and additives using well known pharmaceutical techniques. Pharmaceutically acceptable excipients and additives include non-toxic and chemically compatible fillers, binders, disintegrants, buffers, preservatives, antioxidants, lubricants, flavors, thickeners, colorants, emulsifiers, and the like.

The daily dose of a compound of formula (I) for the treatment of asthma, cough, bronchospasm, inflammatory diseases, migraine and gastrointestinal diseases is 0.1 mg to 20 mg per kilogram body weight per day, preferably 0.5 mg to 15 mg per kilogram body weight daily, and more preferably 0.5 mg to 5 mg per kilogram of body weight per day. For an average body weight of 70 kg, the dosage range is 1 mg to 1500 mg of drug per day, preferably 50 mg to 100 mg per kilogram of body weight per day, administered in a single dose or in two to four divided doses. However, the exact dose must be determined by the physician, and this dose will depend on the efficacy of the compound administered, the age, weight, condition and response of the patient.

The invention is further illustrated by examples which are not to be construed as limiting the scope of the present invention. Alternative routes and analogous structures within the scope of the present invention will be apparent to those skilled in the art.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of (+, -) - 1 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -3-phenylpiperazine, dihydrochloride, 0.25 hydrate.

Η

Chloropyrazine (20, 68 g, 177 mmol) and nickel (bis (diphenylphosphine) ethane) chloride (41.08 g, 77.8 mmol) in dry THF (1.5 L) were mixed and stirred for 80 minutes in a flask (cooled with water bath) under a nitrogen atmosphere. Then, a solution of phenylmagnesium bromide (3 M in Et ₂ O) (103 mL, 309 mmol) was added dropwise slowly to the cooled brick red suspension at room temperature under a nitrogen atmosphere for 3.5 hours. After stirring overnight, the reaction was shown to be complete by TLC. 3 N HCl (100 mL) was added slowly via an addition funnel under nitrogen and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The pH of the aqueous layer was adjusted to 12 with 6 N NaOH, followed by extraction with EtOAc (100 mL, 3x). The organics (THF and EtOAc) were combined and dried over MgSO ₄ , filtered and evaporated to give a solid. The product was purified by flash column chromatography on 300 g flash silica gel eluting with 2.5% EtOAc in CH 2 Cl 2 to give 10.79 g (69 mmol, 39%) of 2-phenylpyrazine, mp 69-70 ° C FAB mass [M +] ⁺ 157;

Found: C, 76.55; H, 5.22; N, 17.71. Calcd for C 10 H 6 N 3 O, C 76.90; H, 5.16; N, 19.93.

To a solution of 2-phenylpyrazine (11.64 g, 74.53 mmol) in acetic acid (58.2 mmol) was added palladium (II) acetate Pd (OAc) ₂ (2.33 g, 9.94 mmol). The mixture was hydrogenated for 4 hours at 50 psi. After completion of the reaction, the catalyst was filtered off and washed with a little acetic acid. The filtrate was evaporated under reduced pressure to give a tan solid which was suspended in deionized water (300 mL) and was adjusted to pH 13 with 20% NaOH solution. The product was then extracted from the aqueous solution with EtOAc (200 mL, 3x), dried over MgSO ₄ , filtered and evaporated to dryness to give 2-phenylpiperazine (7.2 g). An additional 1.6 g of 2-phenylpiperazine was obtained by evaporating the aqueous fraction to a solid and triturating the solid with CH ₂ Cl ₂ . The total yield of 2-phenyl-2-piperazine was 73 mole%. The crude material was crystallized from EtOAc and hexane to allow characterization. Mp 86 ° -88 ° C, FAB mass [M +] ⁺ 163;

Found: C, 74.04; H, 8.66; N, 17.15. Analysis calculated for C _{4 H} Hi N _2, C, 74.04; H, 8.69; N, 17.26.

To a solution of 2-phenylpiperazine (4.0 g, 24.65 mmol) in dry ΟΗ ₂ Ο ₁₂ (200 mL) at -78 ° C was added dropwise a solution of bis (trifluoromethyl) benzyl bromide (4.66) under nitrogen. mL, 24 65 mmol) in CH ₂ C1 ₂ (46, 60 mL). The vessel was kept at -78 ° C and then allowed to gradually warm to room temperature overnight. When the reaction was judged complete by TLC, the reaction mixture was washed with saturated aqueous sodium chloride solution (150 mL, 2x), dried over MgSO ₄ , filtered and evaporated under reduced pressure to a dark solid. The crude product was purified by flash column chromatography (300 g) on flash silica gel eluting with 2.5% MeOH in CH ₂ Cl ₂ to give (+, -) - 1 - [[3,5-bis (trifluoromethyl) phenyl] methyl -3- [beta] 64-Nylpiperazine (6.96 g, 17.92 mol, 72.7 mol%) as an oil. A portion of this oil (0.5 g, 1.287 mmol) was converted to the hydrochloride by dissolving the oil in CH 2 Cl 2 (20 mL) and treatment with 2.3 M HCl-EtOH (1.3 mL, 2.99 mmol). After stirring at room temperature for 10 minutes, the solvents were removed at very low pressure and the residue was dried overnight. Mp 229-233 ° C; FAB Mass [M + 1] ⁺ 389;

Found: C, 48.83; H, 4.28; N, 5.87; Cl, 14.77; F, 24.03. Calculated for C ₁₉ H ₈ N ₂ F ₅ . 2 HCl. 0.25 _H2O C, 48.99; H, 4.43; N, 6.01; Cl, 15.22; F, 24.47.

Example 2

Preparation of (+, -) - 4 - ((3,5-bis (trifluoromethyl) phenyl) methyl] -2-phenyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, trihydrochloride, dihydrate .

To a solution of (+, -) - 1 - ((3,5-bis (trifluoromethyl) phenyl) methyl) -3-phenylpiperazine (0.76 g, 1.975 mmol) in dry CH 2 Cl 2 (15.2 mL) was added at temperature -78 ° C Et ₃ N (0.286 mL, 2.055 mmol) and bromoacetyl bromide (0.179 mL, 2.055 mmol) was added dropwise After stirring at -78 ° C for four hours, the reaction was diluted with CH ₂ Cl ₂ (200 mL), washed with saturated aqueous sodium chloride solution (100 mL, 2x) and dried over MgSO ₄ After filtration, the solvent was evaporated to give a light yellow solid which was used without further purification FAB mass [M + 1] ⁺ 509, 2 ( ⁷⁹ Br).

The product from the previous reaction (1.067 g, 2.096 mmol) was dissolved in CH ₂ Cl ₂ (10.67 mL) and cooled to -78 ° C under nitrogen. To this cooled solution was added 4-amino-1-benzylpiperidine (0.44 mL, 2.11 mmol) and diisopropylethylamine (0.402 mL, 2.3 mmol). The reaction was left under nitrogen overnight and gradually warmed to room temperature. After completion of the reaction, CH ₂ Cl ₂ (300 mL) was added and the organic layer was washed with saturated aqueous sodium chloride solution (100 mL, 2x), dried over MgSO _4, and filtered. The filtrate was evaporated under reduced pressure to give a crude oil which was purified by flash column chromatography (100 g) of flash silica gel eluting with 2.5% NH ₃ -MeOH to 2.5% EtOH in CH ₂ Cl ₂ , to give a pale yellow oil (0.76 g, 1.229 mmol, 59%). A portion of this oil (0.27 g, 0.436 mmol) was converted to the hydrochloride salt by dissolving in CH ₂ C1 ₂ (13.5 mL) and treating with 2.3 M HCI-EtOH (0.938 mL, 2.182 mmol). After stirring at room temperature for 40 minutes, the solvent was evaporated and the residue was dried under reduced pressure overnight, mp 199 ° C to 202 ° C; FAB Mass [M + 1] ⁺ 619.5;

Found: C, 51.73; H, 5.98; N, 7.18; Cl, 13.69; F, 14.75. Calcd. For C ₃₃ H ₃₆ N ₄ OF ₆ . 3 HCl. 2H ₂ O C, 51.87; H, 5.67; N, 7.33; Cl, 13.92; F, 14.91.

Example 3

Using the same procedure as in Example 2, except that (IS, IS) -benzyl-2,5-diazabicyclo [2.2.1] heptanedibromide was used in place of 4-amino-1-benzylpiperidine, the following compound was prepared.

Free form, mp 45 ° C to 47 ° C, HRMS mass calcd 617.2715, found 617.2731.

Example 4

Preparation of (+, -) - 4 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -2-phenyl-N- [1- (phenylmethyl) -4-piperidinyl] -1-piperazinethamine, tetrahydrochloride, monohydrate.

To a solution of (+, -) - 4 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -2-phenyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine ( 0.48 g, 0.776 mmol) in THF (12 mL) was added 10 M BH ₃ .S (CH ₃ ) ₂ (0.388 mL, 3.88 mmol). The mixture was heated under nitrogen in an oil bath at 80 ° C overnight. After completion of the reaction, the excess BH _{3 was} quenched by dropwise addition of MeOH to the cooled solution under nitrogen. The MeOH was evaporated and the residue was redissolved in EtOH (14.4 mL). K ₂ CO ₃ (0.235 g, 1.707 mmol) was then added and the mixture was heated to reflux at 80 ° C for five hours. When the reaction was judged complete by TLC, the solid was filtered off and the filtrate was evaporated under reduced pressure. The residue was redissolved in EtOAc (300 mL), washed with saturated aqueous sodium chloride solution (100 mL) and dried over MgSO ₄ . Filtration and evaporation under reduced pressure gave an oil which was purified by flash column chromatography on flash silica gel (80 g) eluting with 3% v / v NH ₃ MeOH in CH ₂ Cl ₂ to give the desired material as an oil (0.373 g, 0.615) mmol, 79%). A portion of this oil (0.36 g) was converted to the hydrochloride by dissolving the oil in dry CH ₂ Cl ₂ (18 mL) and treatment with 2.3 M HCl-Et-OH (1.3 mL). After stirring for half an hour at room temperature, the solvents were evaporated and the residue was dried under reduced pressure

pressure, Melting point ° C to 241 ° C; FAB mass [M + 1] ^<+> 605.6; Found: C, 51.96; H, 5.83; N, 7.01; Cl, 14.52; F, 18.21. Calculated for C ₃₃ H ₃₉ N ₄ F ₆ . 4 HCl. H ₂ O, C, 51.57; H, 5.77; N, 7.29; Cl, 14.83; F, 18.45.

Example 5

Preparation of 2- (3,4-dichlorophenyl) piperazine Method 1

2- (3,4-dichlorophenyl) pyrazine was prepared as described in Example 1. Mp 118-119 ° C; FAB Mass [M + 1] ^{+ 35} Cl 225.

To a solution of 2- (3,4-dichlorophenyl) pyrazine (10 g, 44.43 mmol) in dry THF (150 mL) was slowly added a solution of DIBAL-H (1 M in THF, 444, via a funnel) over 10 min. 3 ml). After the addition was complete, the color of the solution changed to burgundy red. The solution was allowed to warm slowly to room temperature overnight. After completion of the reaction (TLC control), the reaction was quenched by the slow addition of saturated Na ₂ SO ₄ solution until further H ₂ evolution ceased. A white precipitate formed during stirring for 1 hour. The precipitate was filtered off, washed with THF, dried over MgSO ₄ and evaporated to dryness. The crude material (10 g) was purified by flash chromatography on 300 g of flash silica gel with 7.5% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ expressed in volume percent to give 4.11 g (17.77 mmol), 40% by weight of 2- (3,4-dichlorophenyl) piperazine. Mp 74-76 ° C; FAB Mass [M + 1] ^{+ 35} Cl 231.

Method 2

2- (3,4-dichlorophenyl) piperazine was also synthesized according to the procedure published in J. Med. Chem., 9, 191 (1966).

General method for the synthesis of 2-arylpiperazine derivatives.

R ¹

R ¹ = Cl, H or other substituents, i. _{OCH3, CF3,} Br, I, F, etc.

R ² = Cl, H or other substituents i.e. _{OCH3, CF3,} Br, I, F, etc.

Cleavage of 2- (3,4-dichlorophenyl) piperazine

Step 1

To a solution of piperazine (10.6 g, 45.8 mmol) in methanol (130 mL) was added two equivalents of N-acetyl-L-leucine (15.9 g, 91.5 mmol) and heated together until solids did not dissolve. EtOAc (660 mL) was then added to this solution and allowed to stand overnight at room temperature. The solvent was decanted from the precipitated salt and evaporated under reduced pressure to give 18.5 g of a 3.0:

1.0 enantiomer A to B. The precipitated salt yielded 12.3 g of a colorless solid with a 1.0: 7.1 enriched piperazine enantiomer A to B.

Step 2

The precipitated salt from step 1 was dissolved in 0.5 N NaOH (400 mL) and extracted with ΟΗ ₂ Ο1 ₂ (4 x 150 mL). The organic layers were combined, dried (MgSO 4 and evaporated to give 3.8 g of piperazine as the free base. Recrystallization of the free base twice in hexane (100 mL and 70 mL) afforded 2.5 g of piperazine (98% ee of enantiomer B). ) in the form of colorless crystals.

Step 3

The solvent salt in step 1 was recrystallized in 350 mL EtOAc: methanol (5: 1) to give 15.3 g of the solvent salt. Recrystallization of this salt in 250 mL of EtOAc: methanol (5: 1) gave 9.9 g of the salt from the solvent, which was enriched in the ratio 5.5: 1.0 with the enantiomer of piperazine A to B. The salt was added to 0.5 N NaOH (250 mL) and extracted

CHžCl? (3 x 100 mL). The organic layers were combined, dried (MgSO ₄ ) and evaporated to give 2.8 g of crude free base. Recrystallization from hexane (65 mL) afforded 1.0 g of piperazine (98% ee of enantiomer A).

Analytical procedure for measuring the enantiomeric purity of piperazine

The enantiomeric purity of piperazine was measured by chiral HPLC analysis of the di-tert-butoxycarbonylpiperazine derivative. The di-tert-butoxycarbonylpiperazine derivative was prepared by adding a small sample of piperazine (free base or salt) (0.2 mg) to di-tert-butyl dicarbonate (1 mg) and methanol (0.5 mL). All was heated to 80 ° C for one hour. When the piperazine sample is a salt, triethylamine (20 μΐ) is also added. The derivative was analyzed by HPLC using a ChiralPak AD column with 95: 5 mobile phase, hexane: isopropanol.

Example 6

Preparation of (+, -) - 4 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -2 (3,4-dichlorophenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedure described in the first part of Example 2 except that (+, -) - 1 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -3-phenylpiperazine was used instead of (+, -) - 1 - ((3,5-bis (trifluoromethyl) phenyl) methyl) -3- (3,4-dihydrophenyl) piperazine (Example 5), the bromoacetyl derivative was obtained in 78% yield as a solid, m.p. 146 ° FAB mass [M + 1] ^{+ 3-} Cl 57 7.57 9.

Following the same procedure as described in Part 2, flash chromatography on flash silica gel (70 g), eluting with 4% MeOH in CH ₂ Cl ₂ , gave the title compound as a solid ( M.p. 53-55 ° C; FAB Mass [M + 1] ^{+ 35} Cl 687;

Found: C, 56.98; H, 4.72; N, 8.13; Cl, 10.67; F, 16.30. Calculated for C ₃₃ H ₃₄ N ₄ Cl ₂ F ₆ O. 0.25 _H2O; C, 57.27; H, 5.03; N, 8.10; Cl, 10.25; F, 16.47.

Example 7

Using the same procedure as in Example 2, except that (+, -) - 1 - [(3,5-bis (trifluoromethyl) phenyl) methyl] -3-phenylpiperazine was used (+, -) - 1 - [(3, 5-bis (trifluoromethyl) phenyl) methyl] -3- (3,4-dichlorophenyl) piperazine (Example 5) and (1S, 4S) -2-benzyl-2,5 dihydrobromide was used in place of 4-amino-1-benzylpiperidine -diazabicyclo [2.2.1] heptane, the following compound was obtained

mp 55-57 ° C; FAB mass [M + 1] ^{+ in} view of ^3b Cl 68 5;

Example 8

Preparation of (+, -) - 4 - [(3,5-bis (trifluoromethyl) phenyl) acetyl] -2-phenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

H \ —t

To cooled CH ₂ Cl ₂ (127 mL) containing 2-phenylpiperazine (Example 1, 1.0 g, 6.164 mmol) and N-hydroxybenzotriazole monohydrate (0.874 g, 6.472 mmol) was added Et ₃ N at -20 ° C under nitrogen. (0.9 mL, 6.472 mmol) and N, N-dimethylaminopropylethylcarbodiimide (DEC). The reaction was kept at -20 ° C for one hour and then allowed to gradually warm to room temperature overnight. After stirring for 20 hours, the reaction was complete and CH ₂ Cl ₂ (200 mL) was added. The organic solution was washed with 5% NaHCO ₃ (100 mL) and saturated aqueous sodium chloride solution (100 mL 3x), dried over MgSO ₄ , filtered, concentrated in vacuo to give 2.5 g of crude. product. The product was purified by flash chromatography on flash silica gel (120 g), eluting with 3% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ , expressed in% volume to give a gummy solid (2.08 g, 4.996 mmol, 81%). %). A portion of this solid (1.0 g) was crystallized from hexane and characterized to give a solid, mp 80-82 ° C; FAB Mass [M + 1] ⁺ 417.2;

Calcd. For C ₂₀ H ₁₈ ON ₂ F ₆ : C, 57, 69; H, 4.36; N, 6.73; F, 27.38. Found: C, 57.91; H, 4.55; N, 6.69; F, 27.61.

To a solution of the title compound (1.11 g, 2.642 mmol) in dry CH ₂ Cl ₂ (22.2 mL) at -78 ° C was added diisopropylethylamine (0.483 mL, 2.774 mmol) and then bromoacetyl bromide (0.246) was added dropwise. ml, 2.774 mmol). After stirring at -78 ° C for 7 hours under nitrogen, additional diisopropylethylamine (0.51 mL, 2.9 mmol) and 4-amino-1-benzylpiperidine (0.605 mL, 2.9 mL) were added at -78 ° C. mmol). The reaction mixture was allowed to gradually warm to room temperature. After completion of the reaction, the reaction mixture was diluted with CH ₂ Cl ₂ (150 mL), washed with saturated aqueous sodium chloride solution (50 mL, 3x) and dried over MgSO 4. After filtration, the solvent was evaporated under reduced pressure to give a pale yellow solid which was purified by flash chromatography on flash silica gel (150 g), eluting with 5% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ , expressed as a volume%. to give the title compound as a white solid (0.94 g, 1.453 mmol, 55%), mp 49-52 ° C; FAB Mass [M + 1] ⁺ 647.3;

Analysis calculated for C 4 H ₃ O _{2 36} N ₄ F _6: C, 63.15; H, 5.16; N, 8.66; F, 17.62. Found: C, 62.73; H, 5.77; N, 8.56; F, 17.68.

Example 9

Preparation of (+, -) - 4- [2- (3,5-bis (trifluoromethyl) phenyl) ethyl] -2-phenyl) -N- [1- (phenylmethyl) -4-piperidinyl] -1-piperazethanamine, tetrahydrochloride, hemihydrate

k / NV '' _N ^ _Ph

H> - '. 4 HH · 0.5 H ₂ O

To a solution of the product of Example 16 (0.463 g, 0.72 mmol) in dry THF (21.6 mL) was added a 10 M solution of BH ₃ .S (CH ₃ ) 2 (0.176 mL, 7.16 mmol) at room temperature. in a nitrogen atmosphere. The solution was heated to 80 ° C under nitrogen for 24 hours. After cooling to room temperature, MeOH (5 mL) was slowly added to quench excess BH ₃ .S (CH ₃ ) ₂ . All solvents were evaporated under reduced pressure, and the residue was dissolved in absolute EtOH '(14.1 mL) and K ₂ CO ₃ (0.22 g, 1.58 mmol) was added. The mixture was then heated to 80 ° C under a nitrogen atmosphere for 6.5 hours. After cooling, K ₂ CO _{3 was} filtered off and the EtOH was evaporated to give a residue which was redissolved in EtOAc (150 mL) and washed with saturated sodium chloride solution (50 mL, 2x). The organic solution was dried over MgSO ₄ , filtered and evaporated under reduced pressure to give a solid (0.42 g) which was purified by flash chromatography on flash silica gel (80 g), eluting with 4% MeOH (saturated NH ₃ ). in CH ₂ Cl ₂ , expressed in% volume to give a white solid (0.14 g, 0.227 mmol, 49 mole%).

The material (0.14 g, 0.227 mmol) was treated with CH ₂ C1 ₂ (6.8 mL) and 2.3 M HCl EtO.H (0, 592 ml, 1, 362 mmol). After stirring at room temperature for 10 minutes, the solution was evaporated under very low pressure to give a white solid, mp 182 [M + 1] ⁺ , calculated for C 34 H 41 N 4 F 6,

619.3222.

Calcd. For C 34 H 40 N ₄ F ₆ . 4 HCl H, 5.86; N, 7.24; F, 14.73; Cl, 18.33, H, 6.10; N, 7.21; F, 14.77; Cl, 16.71.

AžC to 190 ° C; HR MS 619, 3235, found

0.5 H ₂ O: C, 52.79; Found: C, 52.58;

Example 10

Preparation of (+, -) -2-phenyl - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] -4 - [(3,4,5-trimethoxyphenyl) acetyl] piperazine hemihydrate

In the same manner as described in Example 8, except that 3,5,5-trimethoxyphenylacetic acid was used in place of 3,5-bis (trifluoromethyl) phenylacetic acid. The title compound was prepared as a solid, mp 53 ° C to 56 ° C, HR MS [M + 1] ⁺ , calcd for C 35 H 45 N 4 O 5, 601, 3390, found

601.3393.

Calcd. For C 35 H 45 N 4 O 5. 0.5 H ₂ O, C, 68, 94; H, 7.43; N, 9.19. Found: C, 69.21; H, 7.53; N, 9.22.

Example 11

Preparation of (+, -) - 2-phenyl-N- [1- (phenylmethyl) -4-piperidinyl] -4- [2- (3,4,5-trimethoxyphenyl) ethyl] -1-piperazinethanamine, tetrahydrochloride, monohydrate

Exactly by the same procedure as described in Example 9 except that the product of Example 10 was used instead of the product of Example 8, the title compound was obtained as a solid, m.p.

Ί6

167 ° C (humid, no sharp melting point); HR MS [M + 1] ⁺ , calcd for C 35 H 49 N 4 O 3, 573, 3805, found 573, 3810.

Calcd. For C 35 H 48 N 4 O 3. 4 HCl. H ₂ O, C, 57.07; H, 7.39; N, 7.61; Cl, 19.25. Found C, 57.16; H, 7.88; N, 7.64; Cl, 18.71.

Example 12

Preparation of (+, -) - 4- [2- [3,5-bis (trifluoromethyl) phenyl] ethyl] -2-phenyl-1 - [[[1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, trihydrochloride

In a manner analogous to the reduction process described in the first part of Example 9, starting from (+, -) - [[3,5-bis (trifluoromethyl) phenyl] acetyl] -3-phenylpiperazine (described in the first part of Example 8). ), (+, -) - 4- [2- [bis (trifluoromethyl) phenyl] ethyl] -2-phenylpiperazine was prepared as a solid after purification by flash chromatography, mp 193 ° C to 195 ° C, FAB mass [ M + 1] ⁺ 403.3. This material (0.38 g, 0.94 mmol) was converted to the bromoacetyl derivative by the same procedure as described in the second step of Example 8. After completion of the reaction, the material was alkylated without isolation with 4-amino-1-benzylpiperidine by the same procedure as described above. in the third step of Example 16. The title compound was obtained as a solid by flash chromatography and then converted to the HCl salt by treatment with HCl / MeOH; mp 214-216 ° C; HR MS [M + l] ^+, calcd for C34H ₃₉ N4OF _{e /} 633.3028, found 633.3034.

Example 13

Preparation of (+, -) - 2-phenyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] -4- [2- (3,4,5-trimethoxyphenyl) ethyl] piperazine

In a manner analogous to the reduction process described in the first part of Example 9, except that (+, -) - 3-phenyl-1- [3,4,5-trimethoxyphenyl) acetyl] piperazine was used as the starting material, a reduced (+, -) - 2-phenyl-4 - [[2- (3,4,5-trimethoxy) phenyl] ethyl] piperazine as a solid after purification by flash chromatography. Mp 160-162 ° C, FAB mass [M + 1] ⁺ 357.4. This material (0.53 g, 1.48 mmol) was converted to the bromoacetyl derivative by the same procedure as described in the second step of Example 8. After completion of the reaction, the material was alkylated without isolation in situ with 4-amino-1-benzylpiperidine by the same procedure. is described in the third step of Example 16. The title compound is obtained and purified by flash chromatography.

Example 14

Preparation of (+, -) - [3,5-bis (trifluoromethyl) benzoyl] -3- (3,4-dichlorophenyl) piperazine

To a cooled solution of CH ₂ Cl ₂ (103 mL) containing 2 (3,4-dichlorophenyl) piperazine (1.15 g, 5.0 mmol), 3,5bis (trifluoromethyl) benzoic acid (1.34 g, 5.09) Et ₃ N (0.711 mL, 5.09 mmol) and N, N-dimethylaminopropylethylcarbodiimide (DEC) (0.967 g, 5 mmol) and N-hydroxybenzotriazole monohydrate (0.688 g, 5.09 mmol) were added at -20 ° C. , 09 mmol) in a nitrogen atmosphere. The reaction was kept at -20 ° C for one hour and then allowed to gradually warm to room temperature overnight. After stirring for 20 hours, the reaction was complete and CH ₂ Cl ₂ (200 mL) was added. The organic solution was washed with 5% NaHCO ₃ (80 mL) and saturated aqueous sodium chloride solution (80 mL, 2x), dried over MgSO ₄ , filtered and evaporated under reduced pressure to give 2.1 g of crude product. The product was purified by flash chromatography on flash silica gel (120 g), eluting with 2% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ to give a foamy solid (1.25 g, 2.65 mmol). , 53 mole%); mp 50-53 ° C; FAB mass [M + 1] + ³⁵ C1 470.9.

Calcd for C ₁₉ H ₁₄ ON ₂ F ₆ Cl ₂ , C, 48, 42; H, 2.99; N, 5.94; F, 24.19; Cl, 15.05. Found: C, 48.57; H, 2.90; N, 5.94; F, 23.90; Cl, 15.03.

Example 15

Preparation of (+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

ABOUT

To a solution of (+/-) - [3,5-bis (trifluoromethyl) benzoyl] -3- (3,4-dichlorophenyl) piperazine (0.6 g, 1.274 mmol) in dry CH ₂ C1 ₂ (12.0 mL) diisopropylethylamine (0.266 mL, 1.53 mmol) was added at -78 ° C, and then bromoacetyl bromide (0.124 mL, 1.40 mmol) was added dropwise. After stirring for 3.5 h at -78 ° C under nitrogen atmosphere, additional diisopropylethylamine (0.234 mL, 1.362 mmol) and 4 amino-1-benzylpiperidine (0.279 mL, 1.362 mmol) were added. The reaction was allowed to gradually warm to room temperature overnight. After completion, dilute with CH ₂ Cl ₂ (200 mL) and wash the organic layer with saturated aqueous sodium chloride solution (80 mL, 3x) and dry over MgSO ₄ . After filtration, the solvent was evaporated under reduced pressure to give a light yellow solid, which was purified by flash column chromatography on flash silica gel (Ϊ50 g), eluting with 5% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ by volume to give the title compound as a white solid (0.55 g, 1.274 mmol,

62 mp), mp 66 ° C up to 69 ° C; FAB- Nost [M + 1] ^{+ 35} C1 701. Calculated for C ₃₃ H ₃₂ O ₂ N ₄ F ₆ C1 ₂ : C, 56.50; H, 4.60; N, 7.99; F, 16.25; Cl, 10.11. Found: C, 56, 57; H, 4.66; N, 7, 94; F, 16.07; Cl, 9.90. Example 16 Using the methods described in Example 14 and

in Example 15, except that suitable amine reagents were used and using parallel synthesis methods, the following compounds were obtained.

Ar = 3,4-dichlorophenyl or phenyl

Z =

637.3

Example 17

Preparation of (+) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dihydrochloride, dihydrate

The compound of Example 15 (100 mg) was separated on a Chiral Pak AD column (5 x 50 cm), eluting with hexane: isopropanol (80:20). The first fraction was evaporated to give 37 mg of enantiomer A, which was converted to the hydrochloride by dissolving in MeOH and adding three equivalents of anhydrous HCl / MeOH, which was allowed to act on the starting material for 20 minutes. Evaporation of the solvent gave a white solid, mp 205 ° C to 220 ° C; [after ^{25 '1} = + 21.1 (MeOH); FAB Mass [M + 1] ^{+ 35} Cl 701.

Calcd. For C ₃ H ₃ O ₂ N ₄ F ₆ Cl 2. 2 HCl. 2 H ₂ O: C,

48, 90; H, 4.73; N, 6.91; F, 14.06; Cl, 17.49. Found: C,

49, 34; H, 4.84; N, 6.82.

HR mass: calculated for [M + 1] ⁺ C 33 H 33 O ₂ N ₄ F ₆ Cl 2: 701, 1885, found 701.1879.

Example 18

Preparation of (-) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dihydrochloride, dihydrate

The compound of Example 15 (100 g) was separated on a Chiral Pak AD column (5 x 50 cm) with hexane: isopropanol (80:20) as eluent. The second fraction was evaporated to give 45 mg of enantiomer B, which was converted to the hydrochloride by dissolving in MeOH and adding three equivalents of anhydrous HCl / MeOH, which was allowed to act on the starting material for 20 minutes. Evaporation of the solvent gave a white solid, mp &gt; 258 ° C; ^[25 where ^'1 = -18.5 (MeOH); FAB Mass [M + 1] ^{+ 35} Cl 701.

Calcd. For C ₃ H ₃ O ₂ N ₄ F ₆ Cl 2. 2 HCl. 2 H ₂ O: C,

48, 90; H, 4.73; N, 6.91; F, 14.06; Cl, 17.49. Found: C, 48.88; H, 4.83; N, 6.71.

HR mass: calculated for [M + 1] ⁺ C 33 H 33 O 2 N ² F 6 Cl 2: 701.1885, found 701.1885.

Example 19

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -1 - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] -4- (3,4,5-trimethoxybenzoyl) piperazine

Using the same procedure as described in Example 14 and Example 15 except that 3,4,5-trimethoxybenzoic acid was used in the coupling reaction in place of 3,5-bis (trifluoromethyl) benzoic acid, the title compound was obtained in 60% yield. m.p. 67 DEG-70 DEG C. FAB mass [M + 1] ^{+ 35} C1 655.

Calcd. For C ₃₄ H ₄₀ N ₅ Cl ₂ , C, 62, 29; H, 6.15; N, 8.54; Cl, 10.81. Found: C, 61.87; H, 6.15; N, 8.46; Cl, 10.62.

Example 20

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- [3- (1-methoxyethoxy) benzoyl] -1 - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedure as described in Example 14 and Example 15, except that 3- (1-methylethoxy) benzoic acid was used in the coupling reaction instead of 3,5-bis (trifluoromethyl) benzoic acid, the title compound was obtained in a yield of 49 M.p. 58-51 ° C; FAB mass [M + 1] ^{+ 35} Cl 62 3.3.

Calculated for C ₃₄ H ₄₀ O ₃ N ₄ Cl ₂ . 0.5 H ₂ O: C, 64.55; H, 6.53; N, 8.86; Cl, 11.20. Found: C, 64.55; H, 6.64; N, 8.92; Cl, 11.26.

Example 21

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- [2-methoxybenzoyl] -1 [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedure as described in Example 14. and Example 15, except that 2-methoxybenzoic acid was used in the coupling reaction instead of 3,5-bis (trifluoromethyl) benzoic acid, the title compound was obtained in 42% yield, temperature mp 71 ° C to 73 ° C, FAB mass [M + 1] ^{+ 35} Cl

595.2.

Example 22

Preparation of (+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -1 - [[(5-phenylmethyl) -2,5-diazabicyclo [2.2.1] heptane] -2-yl] acetyl] piperazine

Using the same procedure as described in Example 14 and Example 15, except that 5-phenylmethyl-2,5-diazabicyclo [2.2.1] heptane was used as the alkylating agent instead of 1-amino-4-benzylpiperidine, the title compound was obtained in yield. 75 mole%, m.p. 75-77 ° C, FAB mass [M + 1] ^{+ 35} Cl

699.2.

Calcd. For C 33 H 30 O 2 N 4 F 6 Cl 2: C, 56.66; H, 4.32; N, 8.01; Cl, 10.14; F, 16.30. Found: C, 56.55; H, 4.41; N, 7.95; Cl, 9.93; F, 16.53.

Example 23

Preparation of (+, -) - 4- [3,5-bis (trifluoromethyl) phenyl] acetyl] -2-phenyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedure as described in Example 14 and Example 15 except that 2- (3,4-dichlorophenyl) piperazine was replaced with 2-phenylpiperazine and 3,5-bis (trifluoromethyl) benzoic acid was used in the coupling reaction. 3,5-bis (trifluoromethyl) phenylacetic acid, the title compound was obtained in 55% yield; mp 49-52 ° C; FAB mass [M + 1] ^{+ 35} Cl 647.3.

Calcd. For C ₃₄ H ₃₆ O ₂ N ₄ F ₆ : C, 63.15; H, 5.61; N, 8.66; F, 17.62. Found: C, 62.73; H, 5.77; N, 8.59; F, 17.68.

Example 24

Preparation of (+, -) - 2-phenyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] -4- [3,4,5- (trimethoxyphenyl)] piperazine

Using the same procedure as described in Example 14 and Example 15 except that 2- (3,4-dichlorophenyl) piperazine was replaced with 2-phenylpiperazine and 3,5-bis (trifluoromethyl) benzoic acid was used in the coupling reaction. 3,4,5-trimethoxyphenylacetic acid, the title compound was obtained as a solid, mp 53 ° C to 56 ° C, HR FAB mass [M + 1] ⁺ calcd for C ₃ H ₄₅ N ₄ O ₅ , 601.3390 ; found 601.3393.

Calculated for Ο ₃₅ Η ₄₄ Ν ₄ Ο ₅ . H ₂ O: C, 68, 94; H, 7.43; N, 9.19. Found: C, 69.21; H, 7.53; N, 9.22.

Example 25

Preparation of {+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2-phenyl-1 [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedure as described in Example 14 and Example 15 except that 2-phenylpiperazine was used instead of 2- (3,4-dichlorophenyl) piperazine, the title compound was obtained in 71% yield as a solid, m.p. 65 ° C to 67 ° C, FAB Mass [M + 1] ^{+ 35} Cl 633, 4.

Calculated for C ₃ H ₃₄ N ₄ O2F ₆ . 0.25 H ₂ 0: C, 62.16; H,

5.46; N, 8.80; F, 17.89. Found: C, 62.00; H, 5.65; N, 8.78; F, 18.08.

Example 26

Preparation of (+, -) - 4- (3,5-dimethylbenzoyl) -2- (3,4-dichlorophenyl) -1 - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

ch ₃

Using the procedures described in Example 14 and Example 15, except that 3,5-dimethylbenzoic acid was used instead of 3,5-bis (trifluoromethyl) benzoic acid, the title compound was obtained as a solid, m.p. 70 [deg.] C .; FAB Mass [M + 1] ^{+ 35} Cl 593.1.

Analysis calculated for C 3 H ₃ N ₄ O _{3d 2} Cl _2: C, 66 77; H, 6.45; N, 9.44; Cl, 11.94. Found: C, 66.64; H, 6.74; N, 9.48; Cl, 11.89.

This racemic compound was resolved into enantiomers A and B by the methods described in Example 17 and Example 18.

Enantiomer A melting point 64-66 ° C; [a] i / · ⁵ = + 26.3

FAB Mass [M + 1] ^{+ 35} Cl 593.3;

Enantiomer B mp 64-66 ° C; [α] _D ²⁵ = -34.8 FAB mass [M + 1] ^{+ 35} Cl 593.3.

Example 27

Using the methods described in Examples 14, 15, 16 and 26, except that the appropriate amine was used, the following compounds were obtained.

CHi

Ar = Ph, JUT ⁰

Ar

H

N.

In ^Ar

OK'

HO

ABOUT

ABOUT

Br ^ -Br £ ^ν ί -> (Λ

N Ar N N- / N Ar

H ^x J ° v,

¹ ~ ^ -Br ³

3,4-dichlorophenyl ^{or phen} Y1 purified in this step

FAB Mass [M + 1] ³⁵ Cl

N - ^ * 0.CH _{and CH3}

Cl Cl

O CH Cl Cl, CH ₃ ch ₃

579.3

579.3

60-62

60-62 _calculate S

525.3230

Example 28

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 - [[[(1- (2-furanylmethyl) -4-piperidinyl] amino] acetyl] piperazine

General Synthesis Method

^{NH NH} 2 t-BOC anhydride

N MeOH k

ph

NH-t -BOC

ph

Pd (OH) 2 / C

MeOH

NH-t -BOC

ArCHO / NaBH ₃ CN MeOH / HOAc ^{1r =} aromatic group

4N

HCl / dioxane

NH-t -BOC

with substituents

Y = aromatic group

Y with substituents

NH2 θ __. θ pF ₃ (CH ₃ )

Λ Br ^ N NAQ ΐ ⁺ M ^to Y ^{Cl C1}

Híigig base

CP ₃ (CH ₃ ) (6) z - \ H o CF ₃ (CH ₃ )

CF ₃ (CH ₃ )

Cl Cl

CH ₂ C1 _:

To a solution of 4-amino-1-benzylpiperidine (9.5 g, 50 mmol) in methanol (150 mL) at -10 ° C was added a solution of di-t-butyl dicarbonate (10.9 g, 50 mmol) in methanol. (60 mL). The mixture was allowed to gradually warm to room temperature overnight. After completion of the reaction, the solvent was evaporated to give a white solid (2) FAB mass [M + 1] ^{+ 35} Cl 2 91.3.

Compound (2) (11.6 g, 40 mmol) was dissolved in methanol (140 mL). To this solution was added Pd (OH) ₂ (20%) on carbon (2.4 g), and the reaction mixture was hydrogenolyzed at 50 psi. After completion of the reaction, the catalyst was filtered off, and the filtrate was evaporated to give compound 3 as a solid (8 g, 40 mmol).

A mixture of compound 3 (0.7 g, 35 mmol) and 2-furaldehyde in MeOH (10 mL) was stirred at room temperature for 10 minutes. Then NaBH ₃ CN (0.5 g, 8 mmol) and acetic acid (1 mL) were added. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, CH ₂ Cl ₂ (50 mL) was added and the mixture was washed with saturated NaHCO ₃ solution (30 mL) and saturated sodium chloride solution (30 mL, 2x). The organic layer after drying over MgSO ₄ was evaporated to give a crude dark solid (Y is 2-furanylmethyl) which was used without further purification. Compound 4 was dissolved in dry CH ₂ Cl ₂ (2 mL) and treated with 4 N HCl in dioxane (5 mL). After stirring at room temperature for two hours, the solvents and excess HCl were evaporated. This afforded Compound 5 as an off-white solid (0.65 g) as the HCl salt.

Compound 5 was converted in situ to the free base using Hunig's base and then reacted with the bromoacetyl key intermediate (6) in the above scheme to give the title compound analogous to the compound obtained as described in Example 15.

Melting point 65-67 ° C; FAB Mass [M + 1] ^{+ 35} Cl 583.

Example 29

The following compounds were obtained in the same manner as in Example 28 and Example 15

FAB and / or Cl mass [M + 1] ^{+ 35} Cl mp ° C

609.1

599.4

97-100

72-74

599.4

583.1

583.1

68-70

64-66

65-67

Example 30

Preparation of (+, -) - 1 - [[[1 - [[[(1, l ^of bi phenyl] -4-yl] methyl] -4-piperidinyl] amino] acetyl] -2- (3, 4 dichlorophenyl) -4- (3,5-dimethylbenzoyl) piperazine

In the same manner as in Example 28, compound (3) (0.69 g, 3 mmol) of Example 28 was mixed with 4 (chloromethyl) biphenyl (0.61 g, 3 mmol) (Y = C ₆ H ₅ -C ₆ H ₅ ) , hunig's base (0.43 g, 3 mmol) in CH ₂ C1 ₂ (10 ml) and vznik90 nuta reaction mixture was stirred for two hours at room temperature. After completion of the reaction, the reaction mixture was diluted with CH ₂ Cl ₂ (50 mL) and washed with saturated aqueous sodium chloride solution (930 mL, 2x). The CH ₂ Cl ₂ layer was dried over MgSO ₄ , filtered and evaporated to a white solid (1 g). The crude product was purified by flash column chromatography on flash silica gel eluting with 2% (v / v) NH ₄ OH-MeOH in CH ₂ Cl ₂ to give compound 4 (Y = C ₆ H ₅ -C ₆ H ₅ ) as in Example 39 as white solid (0.7 g, 64%).

The other two reactions leading to the synthesis of the title compound are the same as in Example 28. FAB mass [M + 1] ^{+ 35} Cl 669; mp 87 ° C to 89 ° C.

Example 31

In the same manner as in Examples 16, 28 and 30, the following compounds were obtained.

^{FAB and / or} «mass _{W + 1r} 3 _{S (; 1}

735.1

770.9

627.2

719.0

737.1

785.0

607.2

71-73

73-75

68-70

70- 72

71- 73

70-72

73-75

611.0

67-69

FAB and / or CI mass [M + 1] ^{+ 35} Cl

715.0

643.2

CH ₃

643

669.0

594.2

639

607.1

69-71

89-91

83-85

87-89

75-76

72-74

72-74

Example 32

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4 - [(4-fluoro-1-naphthalenyl) carbonyl] -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl ] piperazine

General methods of t-BOCanha.

MeOH / -78 ° C

1.4 N HCl dioxane

2. NaOH f'® · pH 10 1-BOC

Bromoacetyl 1 / CH ₂ Cl ₂ bromide

1-BOC N.

Bnzyl N;

2,4-Amino-1-benzyl N, N-Ar ² piperidine

100% o61.5%

ph

OMe * · · <ϊ · ζ ^ ^ΟΜθ c

• S-Oome

OMe

JA.

H = {

Ar '<A _a , "' Ά?

connection%

aromalickeu

Ph or heterocyclic

HOBT-DEC-CH ₂ Cl ₂ kY ^seline

To a cooled solution of 2- (3,4-dichlorophenyl) piperazine (1; Ar ³ - 3,4-dichlorophenyl) (20 g, 86.53 mmol) in MeOH (900 mL) at -78 ° C was added dropwise over added three hours

t.-BOC anhydride The solution was allowed to warm to room temperature gradually under nitrogen atmosphere (19.47 g, 86.53 mmol) in MeOH (263 mL) to evaporate the solvent and dry the residue overnight at very low pressure. to give compound 2 as a white solid. (28 g) (Ar ³ = 3,4-dichlorophenyl) FAB mass [M + 1] ^{, 35} Cl 331.2.

To a solution of compound 2 (23.8 g, 71.85 mmol) in CH 2 Cl 2 (500 mL) cooled to -78 ° C was added dropwise a solution of bromoacetyl bromide (6.88 mL, 79.04 mmol) dropwise over a funnel under nitrogen atmosphere over 10 min. ) in CH 2 Cl 2 (10 mL). After stirring at -78 ° C for three hours, TLC indicated that the reaction was complete. To this cooled solution was added Hunig's base (13.76 mL, 79 mmol) and 4-amino-1-benzylpiperidine (29.30 mL, 143.7 mmol). The reaction mixture was cooled to -78 ° C for one hour and then allowed to gradually warm to room temperature overnight. After completion of the reaction, CH ₂ Cl ₂ (200 mL) was added and the reaction mixture was washed with saturated aqueous sodium chloride solution (200 mL, 3x), dried over MgSO ₄ , filtered and evaporated to give a light brown residue of compound 3 (46 g). (Ar ² = 3,4-dichlorophenyl). Compound 3 was purified by flash column chromatography on 400 g flash silica gel with 3.5% v / v NH ₃ -MeOH in CH ₂ Cl ₂ to give 24.8 g (44.2 mmol, 61.5%) pure. of compound 3 (Ar ² = 3,4-dichlorophenyl). FAB Mass [M + 1] ^{+ 35} Cl 561.3.

To a solution of compound 3 (Ar ² = 3,4-dichlorophenyl) (16 g, 28, 49 mmol) in CH ₂ Cl ₂ (142.5 mL) at 0 ° C was added dropwise a 4 N HCl solution in dioxane at 0 ° C, (71.24 mL, 284.9 mmol). The reaction was allowed to gradually warm to room temperature and stirred for 4 hours. After completion of the reaction, the solvents were evaporated to give a light yellow solid which was dissolved in H ₂ O (400 mL) and the pH was adjusted to 10 with 1 N NaOH. The product was extracted from basic aqueous CH ₂ Cl ₂ solution (200 mL). , 4x), dried over MgSO ₄ , filtered and evaporated to give compound 4 (Ar ² = 3,4-dichlorophenyl) as a pale yellow solid (12.5 g, 27.09 mmol, 95%). FAB Mass [M + 1] ^{+ 35} Cl 461.1. Compound 4 was a key intermediate that was used for coupling with various aromatic acids in the synthesis of many cannon compounds.

To a solution of compound 4 (Ar ² = 3,4-dichlorophenyl) (200 mg, 0.443 mmol) in CH 2 Cl 2 (5 mL) was gradually added 4-fluoro-1-naphthoic acid (84 mg, 0.443) at room temperature. HOBT (58.5 mg, 0.434 mmol), Et 3 N (63.4 mL, 0.455 mmol) and DEC (85 mg, 0.434 mmol). The reaction was stirred overnight under nitrogen at room temperature. After completion of the reaction, the reaction mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous sodium chloride solution (50 mL, 3x), dried over MgSO 4, filtered and evaporated to crude product 5 (Ar ² = 3,4-dichlorophenyl, Ar ¹ - 4-fluoro-1-naphthyl) which was purified by flash column chromatography (50 g flash silica gel) eluting with 4% MeOH (saturated NH 3) in CH ₂ Cl ₂ to give the title compound (0.21 g, 0.331 mmol) , 76.5%). FAB Mass [M + 1] ^{+ 35} Cl 633.2; mp 78-81 ° C.

Example 33

The following compounds were prepared according to the methods described in Example 32. The key intermediate compound 4 in Example 32 (Ar ² = 3,4-dichlorophenyl) was coupled with a suitable aromatic acid to give the cannon compounds. These compounds without melting points were prepared by parallel synthesis.

FAB and / or Cl weight

Cl Cl

[M + 1] ^{+ 35} Cl temperature mp ° C 601 68-70 635 66-69 691 76-78

Cl Cl

633

625

723

73-75

81-83

943

108-11

I

FAB and / or Cl mass [M + 1] ^{+ 35} Cl

mp ° C

66-68

615

87-89

636.1

633.2

621.2

76-Θ0

78-81

70-73

HO O d

Cl Cl

622.18

62-65

FAB and / or CI mass [M + 1] ^{+ 35} <

Cl CI

623.3

655.0

58-61

607

A5-N

Cl Cl o N- <

H ₃ C

618

H O

NJ ^ N N

Cl

Cl

635

ť

Cl Cl

565

705

Example 34

The following compounds were prepared according to the methods described in Example 32. The key intermediate - compound 4 in Example 32 (Ar ² = phenyl) was first prepared and then coupled with the appropriate aromatic acid by the procedure described in Example 32 to give the target compounds. These compounds without melting points were prepared by parallel synthesis

FAB and / or Cl mass [M + 1] ^{+ 35} Cl mp ° C

565.2

CF ₃

525.1

623.1

633.4

565.3 ίοο

Example 35

Preparation of (+, -) - 4- (3,5-dimethylbenzoyl) -1 - [[[(1-phenylmethyl) 4-piperidinyl] amino] acetyl] -2- [4- (trifluoromethyl) phenyl] piperazine, 1, 2 hydrate

3- (4-Trifluoromethylphenyl) -2-piperazinone (1) was prepared according to the procedures published in J. Med. Clin., 9, 191, 1966. To a solution of compound 1 (0.65 g, 2.66 mmol) in anhydrous THF (22 mL) was added dropwise 10 M BH ₃ .S (CH ₃ ) ₂ ( 0.798 ml). The reaction mixture was refluxed for 22 hours. The reaction mixture was then cooled with an ice bath and quenched with MeOH (5 mL). The solvent was evaporated and the residue was dissolved in absolute EtOH (30 mL). To this solution was added anhydrous K ₂ CO ₃ (0.8 g) and the resulting reaction mixture was heated to reflux.

101 to the boiling point for 1 hour, and stirred at room temperature for 1 hour. It was then filtered and evaporated to give an orange solid which was purified by flash chromatography on flash silica gel (24 g) eluting with a gradient of 2.5% to 4% (v / v) MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ to afford gave compound 2 (0.143 g, 24.3%). Compound 2 was followed by the following three steps in the above diagram by the procedure of Example 14 and Example 15 to produce the title compound. FAB Mass [M + 1] ^{+ 35} C1 593.1.

Example 36

The following compounds were prepared according to the methods described in Example 5 (Method 2), Example 14 and Example 15, except that appropriate reagents were used.

102

FAB and / or CI mass [M + 1] ^{+ 35} Cl temperature mp ° C HO r - 'O'> ^CF3 is dimaleat 'OCH ₃ 663 183-185 HO, r-3 O from ^CF 3 → O) dimaleat: MeO 663 195-197 ï »· MeO (ENANTIOMER A) 663.2782 HIKM3 sUlwn-FRV will give f '(ENANTIOMER B) MeO 663.2782 Hn ms iUJovľftf g ^ o / _f = rh ° ^F: _DIMAL 2 · ³ 663 168-170 HOO, ^CH3 555 68-71

MeO

103

Example 37

Preparation of (+, -) - 4- (3,5-bis (trifluoromethyl) benzoyl] -2- (3-hydroxyphenyl) -1 - [([(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dimalate, hemihydrate

To a stirred solution of (+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (3-methoxyphenyl) -1 - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dimalate (1 g, 1.51 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added at 0 ° C a 1 M solution of BH ₃ .S (CH ₃ ) ₂ in CH ₂ Cl ₂ (15 mL) ). The reaction mixture was stirred at 0 ° C to room temperature for 1 hour and then gradually warmed to 80 ° C. It was kept at this temperature for 1 hour. After cooling, the solution was poured into ice-water and the pH was adjusted with NH ₄ OH. The product was extracted from the aqueous solution with CH ₂ Cl ₂ (100 mL, 3x) and the organics were combined, washed with saturated aqueous sodium chloride solution, dried (MgSO ₄ ), filtered and evaporated to give a solid (0.92). g) which was purified by flash silica gel chromatography, eluting with MeOH-CH ₂ Cl ₂ - 28% NH ₄ OH (90: 10: 0.2) to give 0.62 g of the desired compound as a syrup. FAB Mass (M + 1) ^{+ 35} Cl 649.4 To a solution of this syrup (0.61 g, 0.94 mmol) in EtOAc (10 mL) was added a solution of maleic acid (0.218 g, 1.88 mmol) in EtOAc (20 mL) The precipitate was filtered off and recrystallized from MeOH-EtOAc to give the title compound as a white solid (0.58 g) FAB mass [M + 1] ^{+ 35} Cl 649.3; mp 186-187 ° C.

Calculated for C ₃₃ H 4F _{6 3} N4O3. 2 (C 4 H 4 O 4). 0.5 H ₂ O: C,

55, 34; H, 4.87; N, 6.30. Found: C, 55.18; H, 5.14; N, 6.35.

Example 38

104

Preparation of (+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-hydroxyphenyl) -1 - [[[(1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dimalate, hemihydrate

Using the same procedure as in Example 37 except that (+, -) - 4- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-methoxyphenyl) -1 - [[[([ 1-Phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, the title compound was obtained as a white solid as the dimaleate. FAB Mass [M + 1] ^{+ 35} Cl 649.3; mp 175 ° C to 178 ° C

Example 39

Preparation of 2- (R, S) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) 1- [3-hydroxy-1-oxop2 (S) - [[[1- (phenylmethyl) -4] -piperidinyl] amino] propyl] piperazine, hemihydrate

- ^r_ X

The N, N-PlsfO

Cl ₂ L ₂ or ₂

1-BOC-L-serine ·

CF ₃ COOH

105

To a solution of 2- (R, S) - (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) piperazine (1.0 g, 2.753 mmol) in CH ₂ C1 ₂ (10 ml) was added the acid chloride bis (2-oxo-3-oxazolidinyl) phosphine (0.72 g, 2.753 mmol) and Hinig's base (0.48 mL, 2.753 mmol). The reaction mixture was stirred at room temperature for 4 days, then diluted with CH ₂ Cl ₂ (200 mL), washed with saturated sodium chloride solution (80 mL, 3x), dried (MgSO 4), filtered and evaporated to dryness to give 2. 3 g of crude product The crude material was purified by silica gel flash chromatography, eluting with 2% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ , expressed in% volume to give Compound 2 of Example 39 (0.21 g, 0.38 The tBOC protecting group of compound 2 was removed by treatment with CF ₃ COOH in CH ₂ Cl ₂ overnight to give compound 3.

To a solution of compound 3 (180 mg, 0.32 mmol) in MeOH (3.2 mL) was added 1-benzyl-4-piperidone (60 μΐ, 0.32 mmol) at room temperature. After stirring at room temperature for 1 hour, NaBH ₃ CN (26 mg, 0.47 mmol) and acetic acid (32 μΐ) were added. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with H ₂ O (100 mL) and the pH was adjusted to 11 with 1 N NaOH. The product was extracted from the aqueous layer with CH ₂ Cl ₂ (50 mL, 3x), the organic layers were combined, dried (MgSO ₄ ), filtered and evaporated to dryness. The crude material was purified by silica gel flash chromatography, eluting with 4% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ to give the title compound as a white solid. FAB Mass [M + 1] ^{+ 35} Cl 623; mp 69-72 ° C.

Example 40

106

Preparation of 2- (R, S) - (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) 1- [4-methyl-1-oxo-2 (R, S) - [[[1- ( phenylmethyl) -4-piperidinyl] amino] pentyl] piperazine

Following the same procedure as in Example 37 except that (D, L) isoleucine was used instead of serine, the title compound was obtained as a white solid. FAB Mass [M + 1] ^{+ 35} Cl 649.1; mp 68 ° C to 71 ° C.

Example 41

Preparation of (+, -) - N- [2- [2- (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-piperazinyl] -2-oxoethyl] -N- (1-phenylmethyl) -4-piperidinyl] acetamide, hemihydrate

To a solution of (+, -) - 2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1 - [[[(phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine (Example 26) (0.26 g, 0.43 mmol) in anhydrous CH ₂ Cl ₂ (2.5 mL) at -78 ° C was added Hunig's base (0.1 mL, 0.57 mmol) and acetyl chloride (32 mL, 0.45 mmol). The reaction mixture was allowed to gradually warm to room temperature under nitrogen. The reaction was quenched with saturated NaCl solution and extracted twice with CH ₂ Cl ₂ , the organic layers were combined and washed twice with saturated aqueous sodium chloride solution. The organic layer was dried over MgSO ₄ , filtered and evaporated to give a solid which was purified by flash silica gel chromatography, eluting with 4% MeOH (saturated NH ₃ ) in CH ₂ Cl ₂ to give a white solid. 0.22 g (0.35 mmol, 79%) of solid.

FAB Mass [M + 1] ^{+ 35} Cl 635.2; mp 99 ° C to 102 ° C.

Example 42

107

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) 1 - [[[(2-hydroxyethyl) - (1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine , hemihydrate

To a mixture of 4-amino-1-benzylpiperidine (2.13 g, 11.2 mmol) and 2-bromoethanol (0.15 g, 4.08 mmol) in anhydrous CH ₂ Cl ₂ (20 mL) was added Hiinig base ( 2.6 ml, 5.7 mmol). The resulting solution was heated to reflux for 24 hours. After evaporating the CH ₂ Cl ₂ , the crude material was purified by flash silica gel chromatography to give 2 - [[1- (phenylmethyl) 4-piperidinyl] amino] ethanol (0.88 g, 3.8 mmol) in 92% yield. FAB Mass [M + 1] ^{+ 35} Cl 235.

Following the same procedure as in Example 15, except that β-hydroxyethyl-4-amino-1-benzylpiperidine was used instead of 4-amino-1-benzylpiperidine, the title compound was obtained as a white solid after silica gel flash chromatography. FAB Mass [M + 1] ^{+ 35} Cl 637; mp 70 ° C to 73 ° C.

Example 43

Preparation of (+, -) - N- [2- [2- (3,4-Dichlorophenyl) -4- (3,5-dimethylbenzoyl) -1-piperazinyl] -2-oxoethyl] -N, N-dimethylamino-1 - (phenylmethyl) -4-piperidininamino bromide, dimethanolate

To a solution of 4-amino-1-benzylpiperidine (1.47 g, 7.7 mmol) in CF ₃ CH ₂ OH (14 mL) were added 4 A molecular sieves (5 g) and paraformaldehyde (0.51 g, 17 mmol). ). After stirring at room temperature for 1 hour, NaCNBH ₃ (2.5 g, 39.8 mmol) was added and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with H ₂ O. The product was extracted (4: 1) (Et ₂ O: CH ₂ Cl ₂ ). The organic fractions were combined and washed with saturated aqueous sodium chloride solution (2 x), dried over MgSO ₄ , filtered and evaporated to give the crude material which was purified by silica gel flash chromatography to afford

108 gave 4-dimethylamino-1-benzylpiperidine (80% yield). FAB Mass [M + 1] ^{+ 35} Cl 219.

Following the same procedure as in Example 15 except that N, N-dimethyl-4-amino-1-benzylpiperidine was used instead of 4-amino-1-benzylpiperidine, the title compound was obtained as a white solid after silica gel flash chromatography. FAB Mass [M + 1] ^{+ 35} Cl 621.2.

Example 44

Preparation of (+, -) -2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) 1 - [[[methyl- (1-phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

To a solution of 1-benzyl-4-piperidone (1.9 g, 10 mmol) in MeOH (10 mL) was added methylamine (8 mL, 16 mmol) and 3 A molecular sieves. After stirring at room temperature for 1 hour, the reaction was cooled. ice bath and then 4 N HCl in dioxane (2.5 mL, 10 mmol) and NaCNBH 3 (1.2 g, 20 mmol) were added. The resulting reaction mixture was stirred overnight at room temperature. After completion of the reaction, H ₂ O was added and the pH was adjusted to 10 with 50% NaOH solution. The product was extracted with EtOAc (100 mL, 3x) from the aqueous solution and the organic layers were combined. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to give an oil which was purified by silica gel flash chromatography, eluting with 8% MeOH (saturated NH ₃ ) in CH 2 Cl 2, to give 4-methylamino-1-benzylpiperidine (1.77 g, 8.66 mmol, 86%). FAB Mass [M + 1] ^{+ 35} Cl 205.

Following the same procedure as in Example 15, except that 4-methylamino-1-benzylpiperidine was used in place of 4-amino-1-benzylpiperidine, the title compound was obtained as a white solid after silica gel flash chromatography. FAB Mass [M + 1] ^{+ 35} Cl 607.

Example 45

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- (3,5-dimethylbenzoyl) 2-methyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine 0.6 methanol

A solution of 3,4-dichlorophenylacetic acid (5.126 g, 25 mmol) in THF was added dropwise over 15 minutes to a solution of 1.0 M Li (TMS) ₂ / THF (55 mL, 55 mmol) cooled to -78 ° C. in a nitrogen atmosphere. The resulting reaction mixture was stirred in a water bath for 2 hours, then cooled to -78 ° C and then Mel (12 mL) was added. The mixture was allowed to gradually warm to room temperature. After completion of the reaction, the precipitate was filtered off and washed with THF. The precipitate was dissolved in H ₂ O and acidified to pH 2.0, then extracted with EtOAc (100 mL, 3x). The extracts were combined, dried (MgSO 4), filtered and evaporated to give 91% mole yield of 1- (3,4-dichlorophenyl) propionic acid (4.984 g, 22.7 mmol) as an oil. FAB mass [M + 1] ^{+ 35} C1 219.

1- (3,4-Dichlorophenyl) propionic acid (20.23 g,

99.1 mmol) was dissolved in MeOH (200 mL). To this solution was added concentrated H ₂ SO 4 (2 mL) and the solution was heated at reflux for 1 hour. After cooling, the pH of the solution was made basic with NaHCO ₃ and extracted with CH ₂ Cl ₂ . After routine work-up, methyl 1- (3,4-dichlorophenyl) propionate was obtained as an oil.

By the same procedure as described in J. Med. Chem., 9, 191, 1966, methyl-1-bromo-1- (3,4-dichlorophenyl) propionate was brominated with methyl 1- (3,4-dichlorophenyl) -propionate by NBS / CCl 4.

A mixture of methyl 1-bromo-1- (3,4-dichlorophenyl) propionate (3.39 g, 10.9 mmol) and ethylenediamine (7 mL) was stirred at room temperature for 3.5 hours. After completion of the reaction, saturated aqueous sodium chloride solution (100 mL) was added and the product was extracted from the aqueous layer of CH ₂ Cl ₂ (50 mL, 2x). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over MgSO 4, filtered and evaporated to give 95% molar yield of 3- (3,4-dichlorophenyl) -3-methyl-2-piperazinone, which was reduced with LiAlH ₄ (Et ₂ O) at 40 ° C to 2-methyl-2- (3,4-dichlorophenyl) -1-piperidine as described in J. Med. Chem., 9, 191 (1966).

The title compound was prepared according to the same procedure as described in Examples 14 and 15. FAB Mass [M + 1] ^{+ 35} Cl 607.2; mp 58 ° C to 61 ° C.

Example 46

Preparation of (+, -) - 2- (3,4-dichlorophenyl) -4- (4-fluoro-1-naphthalenylcarbonyl) -2-methyl-1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

Using the same procedures as described in Examples 14, 15 and 45, the title compound was obtained as a white solid. FAB Mass [M + 1] ^{+ 35} Cl 647.2; mp 93-96 ° C.

Example 47

Preparation of (+, -) - 4- (3,5-dimethylbenzoyl) -4-hydroxymethyl-2- (3,4-dichlorophenyl) -1 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine

111

Cl

Cl • Si-CN. Znfe z

CH ₂ Cl 2 / RT / 0.5h TL 4383.1984

NH 3 / MeOH 45 ° C. 4h

Cl

ABOUT

CH ₃ 'EI / MeOH ^Hl (15X-30X)

NH 2 HCl + CH 3 COCH 3

α-amino- (3,4-dichlorophenyl) -acetonitrile (3) was prepared as described in Tetrahedron Letters 4383, 1984. Compound (3) was reacted with a solution of HCl in MeOH, which was made from acetyl chloride in MeOH to give to give compound (4). Methyl .alpha.-amino- (3,4-dichlorobenzene) acetate (5) was obtained by hydrolysis (4) at pH 10.5. FAB Mass [M + 1] ^{4 35} C1 243.1.

112

Methyl-α-amino- (3,4-dichlorobenzene) acetate (5) was coupled with O-t-Bu-Nt.-BOC-L-serine to give compound (6) which was deprotected with CF ₃ COOH to give compound (7). FAB mass [M + 1] ^{+ 35} Cl 321. Compound (7) was cyclized with a 25% solution of NaOMe in MeOH expressed as a percentage to give compound (8), FAB mass [M + 1] ^{+ 35} Cl 289.

Compound (8) was reacted with 2-methoxyethoxymethyl chloride (MEMCl) in THF in the presence of Hunig's base to give compound (9) which was reduced with LAH to give compound (10). Compound (10) was coupled with 3,5-dimethylbenzoic acid according to the procedure described in Example 14 to give compound (11).

113

Following the same procedures as described in Example 15, the title compound of the following scheme was obtained.

MEM-0

H

Cl

Cl

Br oh ₂ n- £ n ^ x ^ Br

Cl

ph

Example 48

Preparation of (+, -) - 1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorophenyl) -4 - [[[1- (phenylmethyl) -4-piperidinyl] amino] acetyl] piperazine, dimaleate, monohydrate

1,1-dimethyl-3- (3,4-dichlorophenyl) -1-piperazinecarboxylate, m.p. no. Compound 2 of Example 32 was coupled with the 3,5-dimethylbenzoic acid described in Example 14. The T.-BOC group was removed with trifluoroacetic acid. Following the same procedures as described in Example 15, the title compound was obtained as a white solid; FAB Mass [M + 1] ^{+ 35} Cl 701; mp 170-172 ° C.

114

Industrial use

The compounds of the present invention are industrially useful in the manufacture of medicaments for the treatment of chronic respiratory diseases such as asthma.

Claims (1)

wherein each X is independently O, (H, H), NR _d n is 0 to 2, u is 0 to 2, 1 is 0 to 2, m is 1 and y is 1 to 3, or m is 2 and y provided that no more than one R _c or S; is 0; in the group is other than H; each R _c is independently H, C 1 -C ₆ alkyl, - (CH ₂ ) n 1 -R 1, wherein n ₄ is 1 to 6; R ₄ is OR _a , SR _a , -N R ' Rh ⁰ Ra ni ^and -C-N-Rb OR_ • | = nh Ra O II - ^N " ^C - ^R ". CN, NH, N- * H 116 ο II -Ο — C— Ra Ο R _and II I - Ο-č —N ~~ Rb R b O II —N-C-OR a. _Rc ^of the Cl to C ₆ alkyl or (CH _{2) n} OR _a, provided that no more than one ^of R _c is other than H; each R _a and R _b is independently selected from the group consisting of H, C 1 -C ₆ alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, allyl, or when R _a and R _{b are} attached to the same nitrogen atom, then R _a and R _b together with the nitrogen atom to which they are attached form a 4 to 7 membered ring; R _d is independently selected from the group consisting of H, C 1 -C 6 alkyl, CN, OR _a , phenyl, substituted phenyl, benzyl, or allyl; wherein each R _x and R ₂ are independent of H, C 1 to C 1 C ₆ alkyl, CF ₃ , c ₂ h ₅ , Cl, Br, I, f, NO ₂ , 0R _and CN, NR _and R _b , no about II --- ______ —— No * -Ra -0- 1 -C-R O Ra Rb o Ra O about o R _a II 1 1 II 1 u II II 1 -ABOUT - -C-N-Rb • N-C-OR j , -N-C-Rb t « -C-OR _a - t -C — NR _b ABOUT II w in -with- R _a with R _a —S-NHR _a where R _a is not H at RB et al II -NC-OR _a, or where R, and when the ring, the form R ₂ are on adjacent carbon atoms 117 wherein n ⁷ is 1 or 2; and each R ₃ is independently H, C 1 -C ₆ alkyl, CF ₃ , C ₂ F ₅ , O θ II I alpha.-B a ^C b N QI, Br, I _{t t} or F, OR a. OCF 3. -R a or phenyl; Ar ₃ is heteroaryl or substituted heteroaryl, R1 R ₃ . Ar ₂ is heteroaryl or substituted heteroaryl, 118 each R ₅ is independently selected from the group consisting of H, OH, O '-C' R a C 1 -C ₆ alkyl, - (CH ₂ ) _n R _{4 /} wherein n 1 is 1 to 6, with the proviso that when n 1 is, 1, R ₄ is not OH or NR _and R _b , but also that when R ₅ is C 1 -C ₆ alkyl, then two R ₅ are attached to the nitrogen to form a quaternary salt; and n ₅ is 1 or n ₅ is 2 with the proviso that each n ₅ is independently C 1 -C ₆ alkyl; P 1 and p ₂ are each independently 1 to 4, provided that P 1 and p ₂ are together 2 to 6; R ₆ is heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl,